Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases
Identifieur interne : 000938 ( Pmc/Corpus ); précédent : 000937; suivant : 000939Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases
Auteurs : Kathleen W. Dantzler ; Lauren De La Parte ; Prasanna JagannathanSource :
- Clinical & Translational Immunology [ 2050-0068 ] ; 2019.
Abstract
γδ T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific γδ T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated γδ T‐cell responses to vaccines targeting infections such as
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DOI: 10.1002/cti2.1072
PubMed: 31485329
PubMed Central: 6712516
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PMC:6712516Le document en format XML
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<author><name sortKey="De La Parte, Lauren" sort="De La Parte, Lauren" uniqKey="De La Parte L" first="Lauren" last="De La Parte">Lauren De La Parte</name>
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<author><name sortKey="Jagannathan, Prasanna" sort="Jagannathan, Prasanna" uniqKey="Jagannathan P" first="Prasanna" last="Jagannathan">Prasanna Jagannathan</name>
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>γδ T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific γδ T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated γδ T‐cell responses to vaccines targeting infections such as <italic>Mycobacterium</italic>
,<italic> Plasmodium</italic>
and influenza, and studies in animal models have provided further insight into the association of these responses with improved clinical outcomes. In this review, we examine the evidence for a role for γδ T cells in vaccine‐induced protection against various bacterial, protozoan and viral infections. We further discuss results suggesting potential mechanisms for protection, including cytokine‐mediated direct and indirect killing of infected cells, and highlight remaining open questions in the field. Finally, building on current efforts to integrate strategies targeting γδ T cells into immunotherapies for cancer, we discuss potential approaches to improve vaccines for infectious diseases by inducing γδ T‐cell activation and cytotoxicity.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Transl Immunology</journal-id>
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<title-group><article-title>Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases</article-title>
<alt-title alt-title-type="left-running-head">KW Dantzler <italic>et al</italic>
.</alt-title>
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<contrib-group><contrib id="cti21072-cr-0001" contrib-type="author"><name><surname>Dantzler</surname>
<given-names>Kathleen W</given-names>
</name>
<xref ref-type="aff" rid="cti21072-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="cti21072-cr-0002" contrib-type="author"><name><surname>de la Parte</surname>
<given-names>Lauren</given-names>
</name>
<xref ref-type="aff" rid="cti21072-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="cti21072-cr-0003" contrib-type="author" corresp="yes"><name><surname>Jagannathan</surname>
<given-names>Prasanna</given-names>
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<address><email>prasj@stanford.edu</email>
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<xref ref-type="aff" rid="cti21072-aff-0001"><sup>1</sup>
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<aff id="cti21072-aff-0001"><label><sup>1</sup>
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<named-content content-type="organisation-division">Department of Medicine</named-content>
<institution>Stanford University</institution>
<named-content content-type="city">Stanford</named-content>
<named-content content-type="country-part">CA</named-content>
<country country="US">USA</country>
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<author-notes><corresp id="correspondenceTo"><label>*</label>
<bold>Correspondence</bold>
<break></break>
P Jagannathan, Department of Medicine, Stanford University, 300 Pasteur Drive, Lane Building, Suite L154, Stanford, CA 94305, USA.<break></break>
E‐mail: <email>prasj@stanford.edu</email>
<break></break>
</corresp>
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<pub-date pub-type="epub"><day>28</day>
<month>8</month>
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<date date-type="rev-recd"><day>04</day>
<month>7</month>
<year>2019</year>
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<date date-type="accepted"><day>14</day>
<month>7</month>
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<permissions><pmc-comment> © 2019 Australian and New Zealand Society for Immunology Inc. </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. <italic>Clinical & Translational Immunology</italic>
published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.</copyright-statement>
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<abstract id="cti21072-abs-0001"><title>Abstract</title>
<p>γδ T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific γδ T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated γδ T‐cell responses to vaccines targeting infections such as <italic>Mycobacterium</italic>
,<italic> Plasmodium</italic>
and influenza, and studies in animal models have provided further insight into the association of these responses with improved clinical outcomes. In this review, we examine the evidence for a role for γδ T cells in vaccine‐induced protection against various bacterial, protozoan and viral infections. We further discuss results suggesting potential mechanisms for protection, including cytokine‐mediated direct and indirect killing of infected cells, and highlight remaining open questions in the field. Finally, building on current efforts to integrate strategies targeting γδ T cells into immunotherapies for cancer, we discuss potential approaches to improve vaccines for infectious diseases by inducing γδ T‐cell activation and cytotoxicity.</p>
</abstract>
<kwd-group kwd-group-type="author-generated"><kwd id="cti21072-kwd-0001">cytokines</kwd>
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<kwd id="cti21072-kwd-0004">vaccination</kwd>
<kwd id="cti21072-kwd-0005">Vγ9Vδ2 T cells</kwd>
<kwd id="cti21072-kwd-0006">γδ T cells</kwd>
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<body><sec id="cti21072-sec-0001"><title>Introduction</title>
<p>Although representing only a small percentage of T cells (generally 2–5% of peripheral blood T cells in healthy adults), γδ T cells have increasingly been recognised for their unique roles in establishing and regulating the inflammatory response to infectious diseases. These unconventional T cells have antigen recognition capacity, tissue tropism and cytotoxic functions that are distinct from αβ T cells. γδ T cells are the first T cells to appear in the thymus during foetal thymic ontogeny and, following gene rearrangement, express different T‐cell receptor (TCR) sequences.<xref rid="cti21072-bib-0001" ref-type="ref">1</xref>
TCR diversity is different across different animals, but in humans, subsets expressing different Vγ and Vδ regions localise to different tissues and have differing effector functions. For example, the most abundant subset in human adult peripheral blood is Vγ9Vδ2 cells (also referred to as Vγ2Vδ2) while Vδ1<sup>+</sup>
cells are more common in mucosal tissues.<xref rid="cti21072-bib-0002" ref-type="ref">2</xref>
Existing only in primates, Vγ9Vδ2 cells recognise phosphoantigens induced by stress or pathogens in a process that is dependent on butyrophilin 3A1 (BTN3A1, CD277), a type I glycoprotein in the B7 family.<xref rid="cti21072-bib-0003" ref-type="ref">3</xref>
Other signalling pathways for human γδ T‐cell activation involve TCR interaction with ligands such as F1‐ATPase or endothelial protein C receptor, or additional cell surface receptors such as natural killer group 2 member D (NKG2D) receptors or toll‐like receptors (TLR).<xref rid="cti21072-bib-0004" ref-type="ref">4</xref>
Unlike αβ T cells, all of these pathways are independent of the major histocompatibility complex (MHC). In some animals (e.g. cattle, sheep, chickens), γδ T cells express highly diverse TCRs regardless of tissue localisation, while in others (e.g. mice), almost all γδ T cells in the epidermal layer of the skin (called ‘dendritic epidermal T cells’) express identical γδ TCRs. Interestingly, γδ TCRs are structurally more similar to immunoglobulins than αβ TCRs; the CDR3 lengths of TCR δ chains are long and variable, whereas those of the TCR γ chains are short and constrained.<xref rid="cti21072-bib-0001" ref-type="ref">1</xref>
The presence of TCR chains that use antibody‐like V domains is widely distributed in vertebrates, suggesting a selective pressure for TCR chains that recognise antigen in ways similar to that of antibodies.</p>
<p>Several γδ T‐cell subsets have long been known to rapidly increase in number following systemic infections and to perform numerous roles, including direct anti‐microbial roles, recruitment of innate immune cells and activation of adaptive immune cells.<xref rid="cti21072-bib-0004" ref-type="ref">4</xref>
In many situations, including most bacterial and parasitic infections in humans, it is the Vδ2<sup>+</sup>
T‐cell subset that proliferates, while in some viral infections, Vδ1<sup>+</sup>
T cells expand and exert anti‐microbial activities. Interestingly, γδ T cells also appear to have some level of functional plasticity, enabling them to adapt their function at different points during infection based on TCR signalling and environmental cues. Animal models have further provided support that these cells are not simply biomarkers of infection, but can in fact mediate protection from disease and/or recurrent infection. Despite being known to have an important role in immunity to infectious diseases, γδ T cells have, with the exception of the Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis, largely been ignored in vaccine development. Whether γδ T cells are stimulated directly by the antigen component of the vaccine or indirectly with an appropriate adjuvant, there may be many opportunities to improve vaccine effectiveness by targeting γδ T cells. In this article, we will review the evidence for the role of γδ T cells in vaccine‐induced protection to bacterial, protozoan and viral infections. Many of these diseases, particularly those responsible for the highest mortality and morbidity worldwide – tuberculosis, malaria and HIV – do not yet have an effective vaccine because of rapid pathogen evolution and other biological and technical challenges. However, considering the functional roles of γδ T cells and incorporating them into a vaccine strategy could be an important step towards reducing the devastating impact of these diseases.</p>
</sec>
<sec id="cti21072-sec-0002"><title>Mycobacteria and other bacterial infections</title>
<p>A number of studies have shown expansion of γδ T‐cell populations in response to various bacterial infections, both in humans and in animal models. In humans, γδ T cells accumulate at mucosal epithelial tissues, including the lungs,<xref rid="cti21072-bib-0005" ref-type="ref">5</xref>
and have been shown to rapidly proliferate following infection with <italic>Mycobacterium tuberculosis (Mtb)</italic>
.<xref rid="cti21072-bib-0006" ref-type="ref">6</xref>
, <xref rid="cti21072-bib-0007" ref-type="ref">7</xref>
These responding γδ T cells primarily express Vγ9Vδ2<xref rid="cti21072-bib-0008" ref-type="ref">8</xref>
and recognise <italic>Mtb</italic>
phosphoantigen.<xref rid="cti21072-bib-0006" ref-type="ref">6</xref>
, <xref rid="cti21072-bib-0009" ref-type="ref">9</xref>
Studies testing whether γδ T cells expand in response to the <italic>Mtb</italic>
heat shock protein HSP65 have had somewhat conflicting results, but suggest that while some γδ T‐cell clones can recognise HSP65, the majority of cells respond to other antigens.<xref rid="cti21072-bib-0007" ref-type="ref">7</xref>
, <xref rid="cti21072-bib-0010" ref-type="ref">10</xref>
, <xref rid="cti21072-bib-0011" ref-type="ref">11</xref>
Several <italic>in vitro</italic>
studies have suggested that Vγ9Vδ2 T cells may mediate protection from <italic>Mtb</italic>
. These cells appear to be capable of directly killing extracellular <italic>Mtb</italic>
via release of granulysin and intracellular <italic>Mtb</italic>
via granulysin and perforin.<xref rid="cti21072-bib-0012" ref-type="ref">12</xref>
Mycobacteria‐specific Vγ9Vδ2 T cells from individuals positive for the tuberculosis skin test also produce granzyme A, which indirectly leads to <italic>Mtb</italic>
destruction by stimulating TNFα production by infected macrophages.<xref rid="cti21072-bib-0013" ref-type="ref">13</xref>
In the mouse model, although γδ T cells seem to be less essential to immunity against <italic>Mtb</italic>
,<xref rid="cti21072-bib-0014" ref-type="ref">14</xref>
, <xref rid="cti21072-bib-0015" ref-type="ref">15</xref>
GM‐CSF production by γδ T cells in the lungs seems to play a role in protection and an additive effect between GM‐CSF and IFNγ promoted macrophage control of intracellular bacterial replication.<xref rid="cti21072-bib-0016" ref-type="ref">16</xref>
Clearly, the Vγ9Vδ2 T‐cell subset is important in the human immune response to <italic>Mtb</italic>
, but further work is required to evaluate the role of various cytokines in protection from disease at different timepoints during infection.</p>
<p>γδ T cells also seem to play a role in immunity induced by BCG, the only current vaccination against <italic>Mtb</italic>
. Similarly to natural infection, γδ T‐cell populations expand and produce IFNγ in response to BCG vaccination.<xref rid="cti21072-bib-0017" ref-type="ref">17</xref>
, <xref rid="cti21072-bib-0018" ref-type="ref">18</xref>
, <xref rid="cti21072-bib-0019" ref-type="ref">19</xref>
In fact, IFNγ production by these cells was greater than that of CD4<sup>+</sup>
T cells.<xref rid="cti21072-bib-0019" ref-type="ref">19</xref>
In adults, Vδ2<sup>+</sup>
γδ T cells from BCG‐vaccinated individuals expanded more than cells from non‐vaccinated individuals in response to <italic>in vitro Mtb</italic>
restimulation; this memory‐like phenotype could not solely be attributed to increased helper functions from mycobacteria‐specific memory CD4<sup>+</sup>
T cells.<xref rid="cti21072-bib-0020" ref-type="ref">20</xref>
Given that BCG contains lower levels of phosphorylated nonpeptidic antigens compared to <italic>Mtb</italic>
,<xref rid="cti21072-bib-0021" ref-type="ref">21</xref>
it is unclear whether γδ T cells responding to BCG are recognising the same or different antigens compared to natural infection. Further studies are needed to evaluate the functional role of γδ T‐cell expansion following BCG vaccination, including any role for memory‐like subsets and whether expansion provides protection upon challenge or infection with <italic>Mtb</italic>
. Considering the importance of granulysin, perforin and granzyme A in response to <italic>Mtb</italic>
, it may also be useful to incorporate strategies that elicit these responses into vaccine design.</p>
<p>Studies in non‐human primates further support an important role for γδ T cells in responding to <italic>Mtb</italic>
infection and BCG vaccination. These studies may additionally provide insight into mechanisms driving immunity induced by γδ T‐cell expansion. Non‐human primates serve as a useful model as they also express the Vγ9Vδ2 T‐cell subset, which recognise <italic>Mtb</italic>
, unlike murine γδ T cells which do not recognise phosphoantigen or microbial antigens.<xref rid="cti21072-bib-0015" ref-type="ref">15</xref>
Administration of an <italic>Mtb</italic>
phosphoantigen analog combined with IL‐2 expanded the Vγ9Vδ2 T‐cell population during <italic>Mtb</italic>
infection.<xref rid="cti21072-bib-0022" ref-type="ref">22</xref>
Expanded Vγ9Vδ2 T cells differentiated into effector subpopulations, expressed cytokines such as IFNγ, perforin, granulysin and IL‐12, and led to enhanced pulmonary responses of peptide‐specific CD4<sup>+</sup>
/CD8<sup>+</sup>
T cells.<xref rid="cti21072-bib-0022" ref-type="ref">22</xref>
Importantly, diminished TB lesions and reduced <italic>Mtb</italic>
proliferation were also observed, suggesting a role for expanded/differentiated Vγ9Vδ2 T cells in resistance to <italic>Mtb</italic>
infection.<xref rid="cti21072-bib-0022" ref-type="ref">22</xref>
In another approach, adoptive transfer of autologous Vγ9Vδ2 T cells 1 or 3 weeks after <italic>Mtb</italic>
infection led to significant protection from <italic>Mtb</italic>
, including a rapid recall‐like increase in the pulmonary Vγ9Vδ2 T‐cell subset, decreased <italic>Mtb</italic>
infectious burdens (particularly in the lungs) and reduced pathology.<xref rid="cti21072-bib-0023" ref-type="ref">23</xref>
Following BCG vaccination, Vγ9Vδ2 T cells expanded as early as 4–6 days post‐vaccination with peak levels at 3–5 weeks post‐vaccination; this expansion further coincided with clearance of bacteraemia and immunity to fatal tuberculosis after challenge.<xref rid="cti21072-bib-0024" ref-type="ref">24</xref>
Finally, a prime‐boost approach using phosphoantigen followed by fusion proteins led to expansion of γδ T cells displaying effector memory surface markers and producing cytokines such as IL‐2, IL‐6, IFNγ and TNFα following primary vaccination.<xref rid="cti21072-bib-0025" ref-type="ref">25</xref>
As these cells anergised following boosts whereas αβ T cells expanded,<xref rid="cti21072-bib-0025" ref-type="ref">25</xref>
future studies could investigate whether anergy can be prevented and γδ T‐cell recall responses preserved. Together, the described studies in macaques provide evidence that γδ T cells confer protection from symptomatic <italic>Mtb</italic>
infection and support targeting these cells in vaccination approaches to <italic>Mtb</italic>
.</p>
<p>The γδ T‐cell ontogeny is quite different in other mammals compared to humans and non‐human primates; however, studies in cattle and pigs showed similar responses to those found in humans and macaques. Cattle and other ruminants express large proportions of γδ T cells that decline with age, but remain high relative to human levels.<xref rid="cti21072-bib-0026" ref-type="ref">26</xref>
, <xref rid="cti21072-bib-0027" ref-type="ref">27</xref>
In cattle, γδ T cells rapidly proliferate following infection with <italic>Mycobacterium bovis</italic>
<xref rid="cti21072-bib-0028" ref-type="ref">28</xref>
, <xref rid="cti21072-bib-0029" ref-type="ref">29</xref>
, <xref rid="cti21072-bib-0030" ref-type="ref">30</xref>
or BCG vaccination.<xref rid="cti21072-bib-0031" ref-type="ref">31</xref>
, <xref rid="cti21072-bib-0032" ref-type="ref">32</xref>
Similarly, in pigs, γδ T cells proliferated following vaccination with BCG.<xref rid="cti21072-bib-0033" ref-type="ref">33</xref>
</p>
<p>Other bacterial agents demonstrating γδ T‐cell expansion following infection and vaccination include <italic>Leptospira borgpetersenii</italic>
,<italic> Salmonella enterica</italic>
,<italic> Francisella tularensis</italic>
and <italic>Listeria monocytogenes</italic>
. Similarly to the described response to <italic>Mtb</italic>
, human γδ T‐cell populations, in particular the Vγ9Vδ2 subset, expand following leptospirosis infection.<xref rid="cti21072-bib-0034" ref-type="ref">34</xref>
, <xref rid="cti21072-bib-0035" ref-type="ref">35</xref>
In leptospirosis vaccination studies in cattle, IFNγ‐producing γδ T cells expressing the WC1 co‐receptor expand post‐vaccination and upon <italic>in vitro</italic>
restimulation.<xref rid="cti21072-bib-0036" ref-type="ref">36</xref>
, <xref rid="cti21072-bib-0037" ref-type="ref">37</xref>
, <xref rid="cti21072-bib-0038" ref-type="ref">38</xref>
γδ T cells also expand following salmonella vaccination in chickens and macaques<xref rid="cti21072-bib-0039" ref-type="ref">39</xref>
, <xref rid="cti21072-bib-0040" ref-type="ref">40</xref>
or following salmonella infection in humans.<xref rid="cti21072-bib-0041" ref-type="ref">41</xref>
Furthermore, following salmonella or listeria vaccination in macaques, γδ T cells displaying Vγ9Vδ2 were the major T‐cell subset proliferating.<xref rid="cti21072-bib-0040" ref-type="ref">40</xref>
, <xref rid="cti21072-bib-0042" ref-type="ref">42</xref>
Following subclinical <italic>Listeria monocytogenes</italic>
infection, Vγ9Vδ2 T cells expanded, trafficked to the lungs and intestinal mucosa and evolved into effector cells producing IFNγ, TNFα, Il‐4, Il‐17 and/or perforin.<xref rid="cti21072-bib-0042" ref-type="ref">42</xref>
These cells could then lyse infected target cells and inhibit intracellular bacterial growth, demonstrating a potential role in protection from listeria.<xref rid="cti21072-bib-0042" ref-type="ref">42</xref>
Interestingly, γδ T cells displaying Vγ9Vδ2 expanded in humans infected with <italic>F. tularensis,</italic>
<xref rid="cti21072-bib-0043" ref-type="ref">43</xref>
, <xref rid="cti21072-bib-0044" ref-type="ref">44</xref>
but did not expand following vaccination, perhaps because of different phosphoantigens present.<xref rid="cti21072-bib-0043" ref-type="ref">43</xref>
</p>
<p>In summary, a number of studies have not only demonstrated γδ T‐cell expansion in various bacterial infections, but also possible mechanisms of protection provided by this cell population, including both direct killing and recruitment of other cell types via production of pro‐inflammatory cytokines. Although clear that γδ T cells respond differently based on infectious agent, specific proliferation of the Vγ9Vδ2 subset in response to a number of bacterial pathogens correlates with protection from symptomatic disease. Consequently, upregulating activation and/or functional responses of this subset by vaccination may enhance protection against the agent targeted by immunisation. However, given the γδ T‐cell anergy observed in the described vaccine study combining phosphoantigen with a subunit anti‐tuberculosis vaccine,<xref rid="cti21072-bib-0025" ref-type="ref">25</xref>
as well as prevalent examples of T‐cell exhaustion in other contexts, further work is needed to assess potential mechanisms driving such processes. Timing of interventions could therefore be optimised to induce maximal γδ T‐cell recall responses and promote activation without causing exhaustion.</p>
</sec>
<sec id="cti21072-sec-0003"><title>Malaria infection</title>
<p>In addition to long‐standing evidence that γδ T cells play a role in initial responses to parasitic infections, there is increasing evidence that γδ T cells are important in vaccine‐induced protection from malaria. Studies over the past few decades have shown that γδ T cells (particularly the Vδ2<sup>+</sup>
subset) rapidly expand following infection with the most virulent human malaria parasite, <italic>Plasmodium falciparum (Pf)</italic>
, in children, malaria‐naïve adults and malaria‐experienced adults.<xref rid="cti21072-bib-0045" ref-type="ref">45</xref>
, <xref rid="cti21072-bib-0046" ref-type="ref">46</xref>
, <xref rid="cti21072-bib-0047" ref-type="ref">47</xref>
, <xref rid="cti21072-bib-0048" ref-type="ref">48</xref>
Frequencies of γδ T‐cell subsets, including Vδ2<sup>+</sup>
, Vδ2<sup>−</sup>
, activated CD11c<sup>+</sup>
or CD16<sup>+</sup>
/Tim‐3<sup>+</sup>
γδ T cells, have all been associated with malaria exposure.<xref rid="cti21072-bib-0049" ref-type="ref">49</xref>
, <xref rid="cti21072-bib-0050" ref-type="ref">50</xref>
, <xref rid="cti21072-bib-0051" ref-type="ref">51</xref>
, <xref rid="cti21072-bib-0052" ref-type="ref">52</xref>
, <xref rid="cti21072-bib-0053" ref-type="ref">53</xref>
, <xref rid="cti21072-bib-0054" ref-type="ref">54</xref>
, <xref rid="cti21072-bib-0055" ref-type="ref">55</xref>
, <xref rid="cti21072-bib-0056" ref-type="ref">56</xref>
Higher frequencies and malaria‐responsive cytokine production of Vδ2<sup>+</sup>
T cells correlate with protection against subsequent infection in children living in endemic settings,<xref rid="cti21072-bib-0057" ref-type="ref">57</xref>
, <xref rid="cti21072-bib-0058" ref-type="ref">58</xref>
and <italic>in vitro</italic>
, these cells perform cytotoxic, anti‐parasitic functions.<xref rid="cti21072-bib-0059" ref-type="ref">59</xref>
, <xref rid="cti21072-bib-0060" ref-type="ref">60</xref>
Furthermore, these cells can also act as antigen‐presenting cells,<xref rid="cti21072-bib-0061" ref-type="ref">61</xref>
, <xref rid="cti21072-bib-0062" ref-type="ref">62</xref>
, <xref rid="cti21072-bib-0063" ref-type="ref">63</xref>
, <xref rid="cti21072-bib-0064" ref-type="ref">64</xref>
which may further enhance the response to infection and/or vaccination. In malaria‐naïve volunteers exposed to <italic>Pf</italic>
‐infected mosquitoes, while under chloroquine prophylaxis, γδ T cells expand after infection.<xref rid="cti21072-bib-0065" ref-type="ref">65</xref>
Elevated frequencies of γδ T cells expressing effector memory surface markers and enhanced responsiveness to <italic>Pf</italic>
stimulation persist for over 1 year following experimental infectious challenge.<xref rid="cti21072-bib-0065" ref-type="ref">65</xref>
A recent small study from the same group reported that vaccination with BCG changed the course of experimental malaria infection and that BCG vaccination was associated with altered innate immune activation (including γδ, NK and monocytes) following malaria challenge. Interestingly, expression of the activation marker CD69 on both NK cells and γδ T cells was associated with reduced parasitaemia.<xref rid="cti21072-bib-0066" ref-type="ref">66</xref>
Trends towards increased degranulation and granzyme B production among γδ T cells from BCG‐vaccinated volunteers compared to unvaccinated were also observed.<xref rid="cti21072-bib-0066" ref-type="ref">66</xref>
Together, these results suggest an important role for γδ T cells in mediating protective immunity to malaria.</p>
<p>Although there is not yet an effective vaccine for malaria, preliminary studies testing whole parasite vaccines in humans and mice suggest an important role for γδ T cells in protection from subsequent infection. The malaria vaccine that has advanced farthest to date is the RTS,S vaccine, which is based on the <italic>Pf</italic>
circumsporozoite (CSP) protein and targets the sporozoite and liver stages of infection. Interestingly, RTS,S phase 3 trials in African children detected no significant change in γδ T‐cell frequencies following vaccination and minimal cytokine production by these cells in response to <italic>in vitro</italic>
CSP stimulation.<xref rid="cti21072-bib-0067" ref-type="ref">67</xref>
However, as the authors examined total γδ T cells rather than Vδ2<sup>+</sup>
or other γδ T‐cell subsets, it will be important for future studies to determine whether specific subsets correlate with protection and if so, whether future RTS,S formulations can target these subsets. RTS,S trials in malaria‐naïve populations have generally focused on anti‐CSP antibody studies and CD4<sup>+</sup>
/CD8<sup>+</sup>
T‐cell responses without examining innate populations like γδ T cells. One recent study utilising a systems approach identified natural killer (NK) cell signatures that correlated with and predicted protection,<xref rid="cti21072-bib-0068" ref-type="ref">68</xref>
suggesting that depending on the precise vaccine regimen, innate immune responses could be significant.</p>
<p>In contrast to RTS,S, vaccine formulations using sporozoites (the stage of the parasite injected by the mosquito into the human) have indicated a direct or indirect role for γδ T cells in protection. In malaria‐naïve individuals immunised with the attenuated <italic>Pf</italic>
sporozoite (PfSPZ) vaccine, Vδ2<sup>+</sup>
T cells expanded in a dose‐dependent fashion and frequencies of these cells correlated with protection more significantly than any other cellular immune responses.<xref rid="cti21072-bib-0069" ref-type="ref">69</xref>
, <xref rid="cti21072-bib-0070" ref-type="ref">70</xref>
, <xref rid="cti21072-bib-0071" ref-type="ref">71</xref>
Numbers of memory Vδ2<sup>+</sup>
T cells also correlated with protection in a recent PfSPZ trial in a malaria‐endemic region in Mali.<xref rid="cti21072-bib-0072" ref-type="ref">72</xref>
Finally, when malaria‐naïve individuals were immunised with non‐irradiated PfSPZ combined with chemoprophylaxis (PfSPZ‐cVAC), the frequency of Vδ2<sup>+</sup>
T cells increased in a dose‐dependent manner and memory γδ T cells specifically increased expression of IFNγ and the activation marker CD38.<xref rid="cti21072-bib-0073" ref-type="ref">73</xref>
Additional work is needed to further elucidate the mechanism of Vδ2<sup>+</sup>
T‐cell‐induced protection, as well as to determine whether frequencies of these cells could be used as a biomarker for protection in PfSPZ vaccinations in malaria‐endemic regions.</p>
<p>In the mouse model, results have depended somewhat on the parasite strain used, but generally support γδ T cells as a correlate of natural and vaccine‐induced protection. In the lethal <italic>Plasmodium berghei</italic>
ANKA model, γδ T cells were not required to prevent infection upon blood‐stage challenge following sporozoite vaccination, but did contribute to pre‐erythrocytic immunity by recruiting dendritic cells and CD8<sup>+</sup>
T cells.<xref rid="cti21072-bib-0072" ref-type="ref">72</xref>
These cells may also be important in modulating functional T follicular helper (Tfh) cell and germinal centre B‐cell responses.<xref rid="cti21072-bib-0074" ref-type="ref">74</xref>
In contrast to these indirect roles in protection, γδ T cells appear to act as important effector cells following vaccination with nonlethal <italic>Plasmodium yoelii</italic>
sporozoites.<xref rid="cti21072-bib-0075" ref-type="ref">75</xref>
Results from mice lacking αβ T cells further suggest that γδ T‐cell cytotoxicity may become more effective after interaction with CD4<sup>+</sup>
T cells.<xref rid="cti21072-bib-0075" ref-type="ref">75</xref>
Mice lacking γδ T cells further reveal that these cells may be particularly important in immunity targeting the liver stages of the parasite (before it enters the bloodstream).<xref rid="cti21072-bib-0076" ref-type="ref">76</xref>
Clearly, it will be important to evaluate whether these differing results between murine parasite strains are solely because of differences in the type of immunity induced (i.e. <italic>P. berghei</italic>
‐irradiated sporozoite vaccination induces sterile immunity, while <italic>P. yoelii</italic>
vaccination does not). Interestingly, a vaccine using whole lysate of the promastigote stage of a related parasite, <italic>Leishmania amazonensis</italic>
, led to protection against subsequent infection that was dependent on the presence of γδ T cells.<xref rid="cti21072-bib-0077" ref-type="ref">77</xref>
The mechanisms driving this protection and implications for malaria vaccines, however, are unknown.</p>
<p>In sum, results from vaccination studies targeting malaria (and potentially other parasitic infections such as leishmaniasis) strongly suggest that γδ T cells play an important role in protection from future infection. However, future work is required to definitively show that γδ T cells directly mediate protection rather than act as a biomarker of infection, as well as to determine the mechanism of protection and the role of Vδ2<sup>−</sup>
subsets (if any). In particular, it will be important to assess whether protection is mediated via direct γδ T‐cell cytotoxicity and/or more indirect effects such as antigen presentation, recruitment of other cell types, or stimulation of functional Tfh cells and antibodies. Given that most malaria vaccines in trials, including the leading RTS,S vaccine, use specific antigens rather than whole sporozoites, vaccine effectiveness may be improved by the addition of an adjuvant or other vaccine component that stimulates γδ T‐cell responses. BCG vaccination may be a potential approach based on recent results of increased activation of innate cell populations following CHMI in BCG‐vaccinated individuals;<xref rid="cti21072-bib-0066" ref-type="ref">66</xref>
however, given that this response only occurred in half of the vaccinated volunteers and the sample size was small, further study is warranted.</p>
</sec>
<sec id="cti21072-sec-0004"><title>Viral infections</title>
<p>There is evidence that γδ T cells may play a role in response to viral infections, including influenza virus, HIV and cytomegalovirus (CMV), and that they can directly kill virally infected cells. There is also evidence that these cells can expand <italic>in vivo</italic>
in response to bisphosphonate stimulation and viral vaccination strategies and may contribute to improved outcomes, thereby raising the possibility that these cells could be targeted to play an important role in vaccine‐mediated protection.</p>
<p>Regarding influenza, several studies have shown that phosphoantigen or pamidronate‐activated γδ T cells are capable of inhibiting virus replication by killing influenza‐infected macrophages<xref rid="cti21072-bib-0078" ref-type="ref">78</xref>
and/or lung alveolar epithelial cells.<xref rid="cti21072-bib-0079" ref-type="ref">79</xref>
Phosphoantigen‐activated cells also have non‐cytolytic activities in response to pandemic H1N1, producing IFNγ and expressing inflammatory chemokines.<xref rid="cti21072-bib-0080" ref-type="ref">80</xref>
Relatedly, it was also recently shown that Vγ9Vδ2 T cells can promote CD4<sup>+</sup>
T follicular helper cell differentiation, B‐cell class switching and influenza virus‐specific antibody production in an <italic>in vitro</italic>
co‐culture assay,<xref rid="cti21072-bib-0081" ref-type="ref">81</xref>
suggesting that these cells may provide both a direct cytotoxic and potential synergistic role in the adaptive immune response to influenza.</p>
<p>Although both inactivated and live attenuated influenza vaccine reduce influenza illness and disease complications, live attenuated influenza vaccine has been shown to have superior efficacy in children.<xref rid="cti21072-bib-0082" ref-type="ref">82</xref>
Influenza‐responsive γδ T cells were found to expand following live attenuated, but not inactivated, influenza vaccination,<xref rid="cti21072-bib-0083" ref-type="ref">83</xref>
, <xref rid="cti21072-bib-0084" ref-type="ref">84</xref>
suggesting a potential immunologic correlate for this observation. Despite not proliferating after vaccination, γδ T cells in elderly individuals receiving the inactivated vaccine did increase perforin production and, after <italic>in vitro</italic>
restimulation, proliferated and produced IFNγ and IL‐4.<xref rid="cti21072-bib-0084" ref-type="ref">84</xref>
Similarly, the γδ T‐cell response in the nasal mucosa was attenuated in cigarette smokers relative to non‐smokers,<xref rid="cti21072-bib-0085" ref-type="ref">85</xref>
suggesting these cells may represent a correlate for why smokers respond less well to influenza vaccination. In a murine model of influenza, γδ T cells significantly expand in bronchial alveolar fluid following infection,<xref rid="cti21072-bib-0086" ref-type="ref">86</xref>
and in a humanised mouse model, pamidronate administration to mice reconstituted with human PBMC reduced disease severity and mortality following H1N1 and H5N1 influenza infection. However, pamidronate had no effect in mice reconstituted with Vδ2<sup>−</sup>
depleted cells.<xref rid="cti21072-bib-0087" ref-type="ref">87</xref>
Together, these studies suggest that γδ T cells may not only represent an immunologic correlate of protection from influenza infection and vaccination, but that they might also be a mediator of protection.</p>
<p>Regarding HIV, it has long been known that both the Vδ1<sup>+</sup>
and Vδ2<sup>+</sup>
subsets of γδ T cells have cytotoxic capacity against HIV<xref rid="cti21072-bib-0088" ref-type="ref">88</xref>
, <xref rid="cti21072-bib-0089" ref-type="ref">89</xref>
, <xref rid="cti21072-bib-0090" ref-type="ref">90</xref>
and can inhibit viral replication <italic>in vitro</italic>
. HIV‐infected elite controllers have elevated levels of Vδ2<sup>+</sup>
T cells compared with HIV‐negative controls or HIV‐infected individuals on antiretroviral therapy,<xref rid="cti21072-bib-0091" ref-type="ref">91</xref>
, <xref rid="cti21072-bib-0092" ref-type="ref">92</xref>
suggesting a potential role for these cells in inhibiting viral replication <italic>in vivo</italic>
. γδ T cells may also play a role in controlling viral infection at mucosal barriers. A recent study reported that higher levels of pro‐inflammatory Vδ1<sup>+</sup>
T cells correlated with lower gut‐associated HIV viral load,<xref rid="cti21072-bib-0093" ref-type="ref">93</xref>
and another study in rhesus macaques found that levels of CD8<sup>+</sup>
Vδ2<sup>+</sup>
T cells in the female reproductive tract correlated with lower SIV viral loads.<xref rid="cti21072-bib-0094" ref-type="ref">94</xref>
Vδ1<sup>+</sup>
T cells expanding in HIV‐infected individuals may also protect from other infections. For example, Vδ1<sup>+</sup>
T cells producing IFNγ and IL‐17A responded to <italic>Candida albicans</italic>
<xref rid="cti21072-bib-0095" ref-type="ref">95</xref>
and further expanded upon influenza vaccination combined with the MF59 adjuvant.<xref rid="cti21072-bib-0096" ref-type="ref">96</xref>
</p>
<p>Individuals with chronic HIV infection have been found to have Vδ2<sup>+</sup>
T‐cell depletion and dysfunction in response to phosphoantigenic stimulation.<xref rid="cti21072-bib-0097" ref-type="ref">97</xref>
It is possible, however, that some of these cells are not dysfunctional but rather have different functions. For example, He <italic>et al</italic>
. identified a population of CD16<sup>+</sup>
Vδ2<sup>+</sup>
T cells that had decreased responses to phosphoantigens but increased capacity for antibody‐dependent cellular cytotoxicity (ADCC). A decline in this population was associated with faster disease progression, while no decline was observed in individuals with controlled infection.<xref rid="cti21072-bib-0098" ref-type="ref">98</xref>
Administration of zoledronic acid with IL‐2 in HIV‐infected, antiretroviral naïve patients was associated with Vδ2<sup>+</sup>
T‐cell expansion, dendritic cell activation and increased HIV‐specific CD8<sup>+</sup>
T‐cell responses.<xref rid="cti21072-bib-0099" ref-type="ref">99</xref>
It was also recently shown that γδ T cells can be isolated from antiretroviral suppressed, HIV‐infected individuals and that these cells can kill autologous HIV‐infected CD4<sup>+</sup>
T cells. In addition, these cells could expand <italic>ex vivo</italic>
following pamidronate stimulation and could significantly reduce viral replication, suggesting a potential role for these cells to clear HIV infection from latent reservoirs.<xref rid="cti21072-bib-0100" ref-type="ref">100</xref>
</p>
<p>Even though HIV vaccine trials to date have not investigated any changes in γδ T‐cell populations, an intriguing study looked at canarypox as a vector for HIV antigens and, after <italic>in vitro</italic>
expansion, identified a Vγ9<sup>+</sup>
population (specific for canarypox, not HIV antigens) that produced IFNγ.<xref rid="cti21072-bib-0101" ref-type="ref">101</xref>
These results suggest that in addition to adjuvants, vaccine vectors could be used to target γδ T‐cell responses.</p>
<p>Finally, in the context of CMV infection, oligoclonal γδ (primarily Vδ2<sup>−</sup>
) T cells expand and differentiate into effector/memory cells.<xref rid="cti21072-bib-0102" ref-type="ref">102</xref>
, <xref rid="cti21072-bib-0103" ref-type="ref">103</xref>
, <xref rid="cti21072-bib-0104" ref-type="ref">104</xref>
, <xref rid="cti21072-bib-0105" ref-type="ref">105</xref>
Expansion of Vδ2<sup>−</sup>
T cells is associated with viral clearance both in immunosuppressed<xref rid="cti21072-bib-0102" ref-type="ref">102</xref>
, <xref rid="cti21072-bib-0106" ref-type="ref">106</xref>
, <xref rid="cti21072-bib-0107" ref-type="ref">107</xref>
and in healthy populations.<xref rid="cti21072-bib-0102" ref-type="ref">102</xref>
, <xref rid="cti21072-bib-0107" ref-type="ref">107</xref>
These cells likely contribute to viral clearance via effector functions such as cytotoxicity and IFNγ/TNFα production,<xref rid="cti21072-bib-0108" ref-type="ref">108</xref>
‘antibody‐dependent cell‐mediated inhibition’,<xref rid="cti21072-bib-0109" ref-type="ref">109</xref>
and enhanced cytotoxicity via sensing of IL‐18 from virus‐infected cells.<xref rid="cti21072-bib-0110" ref-type="ref">110</xref>
During secondary infection, cells proliferate and resolve infection faster, suggesting a memory‐like phenotype.<xref rid="cti21072-bib-0102" ref-type="ref">102</xref>
Several studies in mice have shown that (1) γδ T cells are capable of protecting αβ T‐cell‐deficient mice against CMV‐induced pathology and (2) adoptive transfer of CMV‐induced γδ T cells provides long‐term protection in immunodeficient mice.<xref rid="cti21072-bib-0111" ref-type="ref">111</xref>
, <xref rid="cti21072-bib-0112" ref-type="ref">112</xref>
These results suggest that γδ T cells are important mediators of protection against CMV and support approaches using adoptive transfer of effector/memory γδ T cells or targeting γδ T cells in future CMV vaccine trials. The possibility of inducing exhausted γδ T cells would need to be considered, however, as CMV infection has both been shown to result in higher numbers of these cells.<xref rid="cti21072-bib-0113" ref-type="ref">113</xref>
</p>
<p>In sum, results from <italic>in vitro</italic>
and natural infection studies suggest an important role for γδ T cells in controlling influenza, HIV and CMV viral replication. Targeting γδ T cells through stimulation could provide an important adjuvant‐type role in vaccination and/or cure‐related strategies for viral infections.</p>
</sec>
<sec id="cti21072-sec-0005"><title>Conclusions</title>
<p>Across the different bacterial, protozoan and viral infections examined (summarised in Table <xref rid="cti21072-tbl-0001" ref-type="table">1</xref>
), there are clear patterns of γδ T‐cell expansion, particularly of the Vδ2<sup>+</sup>
subset, in response to both infection and vaccination. In several contexts, including infection with <italic>Mtb</italic>
, malaria, influenza and HIV and vaccination with BCG, PfSPZ and live attenuated influenza, γδ T cells are associated with protection. Further, evidence so far supports a role for γδ T cells in mediating protection via direct killing and other mechanisms. Studies in animal models, such as BCG vaccination in macaques and PfSPZ vaccination in mice, are beginning to shed light on direct mechanisms of protection <italic>vs</italic>
. stimulation of other immune cells that mediate protection. Clearly, future work is needed to further elucidate these mechanisms, as well as the host and infection‐mediated factors that influence responsivity of γδ T cells and the relevant differences between responses to natural infection compared to response to vaccination. As new vaccine formulations targeting these diseases progress through development, the question of whether to induce γδ T cells or γδ T‐cell subsets will become an important consideration. In fact, this approach is already being implemented in cancer, whether via administration of Vγ9Vδ2 T‐cell agonists<xref rid="cti21072-bib-0114" ref-type="ref">114</xref>
or using BCG to stimulate Vγ9Vδ2 T cells as treatment for bladder cancer.<xref rid="cti21072-bib-0115" ref-type="ref">115</xref>
, <xref rid="cti21072-bib-0116" ref-type="ref">116</xref>
Approaches incorporating γδ T cells into strategies targeting B‐ or T‐cell responses have also been promising so far. For example, as previously mentioned, a study testing a subunit tuberculosis vaccine combined with phosphoantigen observed a robust γδ T‐cell response, including expression of effector memory markers, following primary vaccination.<xref rid="cti21072-bib-0025" ref-type="ref">25</xref>
Finally, another intriguing approach is to expand functional γδ T cells <italic>ex vivo</italic>
, as has been tested with effector cells capable of inhibiting HIV replication<xref rid="cti21072-bib-0100" ref-type="ref">100</xref>
and <italic>Mtb</italic>
infection.<xref rid="cti21072-bib-0023" ref-type="ref">23</xref>
</p>
<table-wrap id="cti21072-tbl-0001" xml:lang="en" orientation="portrait" position="float"><label>Table 1</label>
<caption><p>Human γδ T‐cell responses to bacterial, viral and protozoan infections and corresponding vaccinations</p>
</caption>
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<thead valign="top"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="top" rowspan="1" colspan="1">Author, year</th>
<th align="left" valign="top" rowspan="1" colspan="1">Agent</th>
<th align="left" valign="top" rowspan="1" colspan="1">Cohort</th>
<th align="left" valign="top" rowspan="1" colspan="1">γδ T‐cell subset</th>
<th align="left" valign="top" rowspan="1" colspan="1">Impact of infection/vaccination on γδ T‐cell activation</th>
<th align="left" valign="top" rowspan="1" colspan="1">Associations between γδ T‐cell features and function/clinical outcomes</th>
</tr>
</thead>
<tbody><tr><td align="left" colspan="6" rowspan="1">Bacterial</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Barnes <italic>et al</italic>
. 1992<xref rid="cti21072-bib-0006" ref-type="ref">6</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Mycobacterium tuberculosis (Mtb)</italic>
</td>
<td align="left" rowspan="1" colspan="1">Adults with tuberculous infection</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Strong correlation between expansion of γδ T cells and <italic>Mtb</italic>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Mtb</italic>
‐reactive γδ T cells produced IFNγ, GM‐CSF, IL‐3 and TNFα; secretion of macrophage‐activating cytokines may contribute to resistance against mycobacterial infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Dieli <italic>et al</italic>
. 2001<xref rid="cti21072-bib-0012" ref-type="ref">12</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Mtb</italic>
</td>
<td align="left" rowspan="1" colspan="1">PPD‐positive adults</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2 T lymphocytes efficiently kill extracellular and intracellular <italic>Mtb</italic>
through release of granulysin and perforin</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Spencer <italic>et al</italic>
. 2013<xref rid="cti21072-bib-0013" ref-type="ref">13</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Mtb</italic>
</td>
<td align="left" rowspan="1" colspan="1">PPD‐positive, HIV‐negative adults</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Infected macrophages co‐cultured with γδ T cells produced TNFα and inhibited intracellular mycobacterial growth</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Hoft <italic>et al</italic>
. 1998<xref rid="cti21072-bib-0020" ref-type="ref">20</xref>
</td>
<td align="left" rowspan="1" colspan="1">Bacille Calmette–Guérin (BCG)</td>
<td align="left" rowspan="1" colspan="1">Adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T‐cell expansion after vaccination; memory‐like immune responses after <italic>in vitro</italic>
restimulation</td>
<td align="left" rowspan="1" colspan="1">Enhanced responsiveness after BCG vaccination suggests that γδ T cells are important to secondary immune response</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Mazzola <italic>et al</italic>
. 2007<xref rid="cti21072-bib-0017" ref-type="ref">17</xref>
</td>
<td align="left" rowspan="1" colspan="1">BCG</td>
<td align="left" rowspan="1" colspan="1">Infants</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Remarkable expansion of γδ T cells in response to vaccination</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Tastan <italic>et al</italic>
. 2005<xref rid="cti21072-bib-0018" ref-type="ref">18</xref>
</td>
<td align="left" rowspan="1" colspan="1">BCG</td>
<td align="left" rowspan="1" colspan="1">Infants</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Significant increase in γδ T cells following vaccination at birth</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Zufferey <italic>et al</italic>
. 2013<xref rid="cti21072-bib-0019" ref-type="ref">19</xref>
</td>
<td align="left" rowspan="1" colspan="1">BCG</td>
<td align="left" rowspan="1" colspan="1">Adults, children and infants</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">γδ T cells (particularly Vδ2<sup>+</sup>
subset) from infants and children immunised with BCG expand after <italic>in vitro</italic>
restimulation</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
T cells produce IFNγ following BCG vaccination</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Barry <italic>et al</italic>
. 2006<xref rid="cti21072-bib-0034" ref-type="ref">34</xref>
</td>
<td align="left" rowspan="1" colspan="1">Unknown <italic>Leptospira</italic>
species</td>
<td align="left" rowspan="1" colspan="1">Adult case study</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Patient had an almost tenfold increase of γδ T cells above baseline following infection</td>
<td align="left" rowspan="1" colspan="1">γδ T‐cell expansion parallels patient's symptoms; unable to determine whether γδ T cells play role in resolution of or exacerbation of symptomatic disease</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Klimpel <italic>et al</italic>
. 2003<xref rid="cti21072-bib-0035" ref-type="ref">35</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Leptospira interrogans</italic>
</td>
<td align="left" rowspan="1" colspan="1">Adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Preferential <italic>in vitro</italic>
expansion of TCR+ γδ T cells in cultures exposed to high numbers of <italic>Leptospira</italic>
</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Workalemahu <italic>et al</italic>
. 2014<xref rid="cti21072-bib-0040" ref-type="ref">40</xref>
</td>
<td align="left" rowspan="1" colspan="1">lytB‐ aroA‐ <italic>Salmonella enterica</italic>
serovar Typhimurium SL7207</td>
<td align="left" rowspan="1" colspan="1">Adults</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1">LytB negative vaccines stimulated large <italic>ex vivo</italic>
expansions of Vγ9Vδ2 T cells from human donors</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Poquet <italic>et al</italic>
. 1998<xref rid="cti21072-bib-0043" ref-type="ref">43</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Francisella tularensis</italic>
and <italic>F. tularensis</italic>
live vaccine strain (LVS)</td>
<td align="left" rowspan="1" colspan="1">Adults</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1">Massive increase in Vγ9Vδ2 T cells during infection; minor or no increase in Vγ9Vδ2 T cells after live strain vaccination</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" colspan="6" rowspan="1">Protozoan</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Ho <italic>et al</italic>
. 1990<xref rid="cti21072-bib-0045" ref-type="ref">45</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Plasmodium falciparum (Pf)</italic>
</td>
<td align="left" rowspan="1" colspan="1">Individuals (age not reported) with acute infection</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells expand after infection and remain elevated for at least 4 weeks</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Roussilhon <italic>et al</italic>
. 1994<xref rid="cti21072-bib-0048" ref-type="ref">48</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults with acute infection</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells expand and remain elevated for months; subset proliferates <italic>in vitro</italic>
in response to <italic>Pf</italic>
schizont extract</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Hviid <italic>et al</italic>
. 2001<xref rid="cti21072-bib-0046" ref-type="ref">46</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children with acute infection</td>
<td align="left" rowspan="1" colspan="1">Vδ1<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Vδ1<sup>+</sup>
T cells increase after treatment</td>
<td align="left" rowspan="1" colspan="1">Expanded Vδ1<sup>+</sup>
T cells produce pro‐inflammatory cytokines</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">D'Ombrain <italic>et al</italic>
. 2008<xref rid="cti21072-bib-0057" ref-type="ref">57</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Production of IFNγ following <italic>in vitro Pf</italic>
stimulation associated with immunity to symptomatic infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Cairo <italic>et al</italic>
. 2014<xref rid="cti21072-bib-0051" ref-type="ref">51</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Neonates in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Neonates exposed to placental malaria had increased proportions of central memory Vγ2Vδ2 cells in cord blood</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Jagannathan <italic>et al</italic>
. 2014<xref rid="cti21072-bib-0054" ref-type="ref">54</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Repeated infection associated with loss and dysfunction of Vδ2<sup>+</sup>
cells, including increased expression of immunoregulatory genes (Tim3, CD57, CD16)</td>
<td align="left" rowspan="1" colspan="1">Loss and dysfunction of pro‐inflammatory Vδ2<sup>+</sup>
cells associated with clinical tolerance to infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Farrington <italic>et al</italic>
. 2016<xref rid="cti21072-bib-0052" ref-type="ref">52</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">High prior malaria exposure leads to increased CD16 expression on Vδ2<sup>+</sup>
T cells</td>
<td align="left" rowspan="1" colspan="1">High prior malaria exposure leads to lower Vδ2<sup>+</sup>
T‐cell functional responses; antimalarial chemoprevention associated with enhanced Vδ2<sup>+</sup>
cytokine production</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Jagannathan <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0058" ref-type="ref">58</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Repeated infection associated with loss and dysfunction of Vδ2<sup>+</sup>
cells, including reduced proliferation</td>
<td align="left" rowspan="1" colspan="1">Higher pro‐inflammatory cytokine production associated with protection from subsequent infection and increased odds of symptoms once infected</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Schofield <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0055" ref-type="ref">55</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Children in malaria‐endemic region</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Tim‐3 upregulated on γδ T cells following acute infection; frequency of Tim‐3<sup>+</sup>
γδ T cells higher among malaria‐exposed individuals compared to healthy controls</td>
<td align="left" rowspan="1" colspan="1">Individuals with asymptomatic malaria infection have higher proportions of Tim‐3<sup>+</sup>
γδ T cells</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Taniguchi <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0056" ref-type="ref">56</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Adults and children with uncomplicated malaria</td>
<td align="left" rowspan="1" colspan="1">Non‐Vδ2</td>
<td align="left" rowspan="1" colspan="1">Non‐Vδ2 T cells expand during infection</td>
<td align="left" rowspan="1" colspan="1">Non‐Vδ2 T cells produce IL‐10 and IFNγ</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Bediako <italic>et al</italic>
. 2019<xref rid="cti21072-bib-0049" ref-type="ref">49</xref>
</td>
<td align="left" rowspan="1" colspan="1"><italic>Pf</italic>
</td>
<td align="left" rowspan="1" colspan="1">Malaria‐exposed adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">CD11c<sup>+</sup>
γδ T cells expanded in individuals with high numbers of malaria episodes and distinguished between high <italic>vs</italic>
. low malaria episode groups</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Teirlinck <italic>et al</italic>
. 2011<xref rid="cti21072-bib-0065" ref-type="ref">65</xref>
</td>
<td align="left" rowspan="1" colspan="1">Controlled human malaria infection (CHMI)<sup>+</sup>
chemoprophylaxis</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells express effector memory phenotype</td>
<td align="left" rowspan="1" colspan="1">γδ T cells produce IFNγ even a year after infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Seder <italic>et al</italic>
. 2013<xref rid="cti21072-bib-0071" ref-type="ref">71</xref>
</td>
<td align="left" rowspan="1" colspan="1">Attenuated PfSPZ vaccination</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells expanded following vaccination</td>
<td align="left" rowspan="1" colspan="1">Higher frequencies of γδ T cells correlate with protection after controlled human malaria infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Ishizuka <italic>et al</italic>
. 2016<xref rid="cti21072-bib-0069" ref-type="ref">69</xref>
</td>
<td align="left" rowspan="1" colspan="1">Attenuated PfSPZ vaccination</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">γδ T cells expanded following immunisation</td>
<td align="left" rowspan="1" colspan="1">Higher frequencies of γδ T cells correlate with protection after controlled human malaria infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Mordmuller <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0073" ref-type="ref">73</xref>
</td>
<td align="left" rowspan="1" colspan="1">Non‐irradiated PfSPZ vaccination + chemoprophylaxis</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1">Dose‐dependent increase in the frequency of circulating γδ T cells (primarily the Vγ9Vδ2 subset)</td>
<td align="left" rowspan="1" colspan="1">Memory γδ T cells increase IFNγ secretion and expression of the activation marker CD38 post‐vaccination</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Zaidi <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0072" ref-type="ref">72</xref>
</td>
<td align="left" rowspan="1" colspan="1">Irradiated PfSPZ vaccination</td>
<td align="left" rowspan="1" colspan="1">Malaria‐exposed adults</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
T cells expanded following vaccination</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
T cells significantly elevated among vaccinated individuals who remained uninfected during transmission season; number of memory Vδ2<sup>+</sup>
T cells associated with protection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Walk <italic>et al</italic>
. 2019<xref rid="cti21072-bib-0066" ref-type="ref">66</xref>
</td>
<td align="left" rowspan="1" colspan="1">CHMI following BCG vaccination</td>
<td align="left" rowspan="1" colspan="1">Malaria‐naïve adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">In half the BCG‐vaccinated individuals, CD69‐expressing γδ T cells expanded</td>
<td align="left" rowspan="1" colspan="1">Trends towards increased degranulation and granzyme B production among γδ T cells from BCG‐vaccinated volunteers compared to unvaccinated</td>
</tr>
<tr><td align="left" colspan="6" rowspan="1">Viral</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Fenoglio <italic>et al</italic>
. 2011<xref rid="cti21072-bib-0096" ref-type="ref">96</xref>
</td>
<td align="left" rowspan="1" colspan="1">Influenza virus vaccination with MF59 adjuvant</td>
<td align="left" rowspan="1" colspan="1">HIV‐positive and HIV‐negative adults</td>
<td align="left" rowspan="1" colspan="1">Vδ1<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1"><italic>In vivo</italic>
expansion of Vδ1<sup>+</sup>
γδ T cells in HIV+ individuals following vaccination</td>
<td align="left" rowspan="1" colspan="1">Expanded population produces anti‐fungal cytokines (may contribute to defence against opportunistic infections by compensating for impairment of CD4<sup>+</sup>
T cells)</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Hoft <italic>et al</italic>
. 2011<xref rid="cti21072-bib-0083" ref-type="ref">83</xref>
</td>
<td align="left" rowspan="1" colspan="1">Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (TIV)</td>
<td align="left" rowspan="1" colspan="1">Children</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells induced by LAIV, but not TIV</td>
<td align="left" rowspan="1" colspan="1">γδ T cells induced by vaccination with LAIV develop memory responses and inhibit viral replication</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Horvath <italic>et al</italic>
. 2012<xref rid="cti21072-bib-0085" ref-type="ref">85</xref>
</td>
<td align="left" rowspan="1" colspan="1">LAIV</td>
<td align="left" rowspan="1" colspan="1">Adult smokers and non‐smokers</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">γδ T cells migrate to the lung following influenza infection in response to chemokines; cell population with characteristics of γδ T cells increases following LAIV vaccination</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Re <italic>et al</italic>
. 2006<xref rid="cti21072-bib-0084" ref-type="ref">84</xref>
</td>
<td align="left" rowspan="1" colspan="1">Trivalent TIV</td>
<td align="left" rowspan="1" colspan="1">Elderly individuals</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Proliferative capacity of γδ T cells decreased and number of differentiated γδ T cells with effector/memory functions increased following vaccination</td>
<td align="left" rowspan="1" colspan="1">γδ T cells showed increased production of perforins after vaccination</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Fausther‐Bovendo <italic>et al</italic>
. 2008<xref rid="cti21072-bib-0089" ref-type="ref">89</xref>
</td>
<td align="left" rowspan="1" colspan="1">Human Immunodeficiency Virus (HIV)</td>
<td align="left" rowspan="1" colspan="1">HIV‐1‐infected adults</td>
<td align="left" rowspan="1" colspan="1">Vδ1<sup>+</sup>
</td>
<td align="left" rowspan="1" colspan="1">Expansion of Vδ1<sup>+</sup>
T cells in individuals with HIV infection</td>
<td align="left" rowspan="1" colspan="1">Strong cytolytic capacities of Vδ1<sup>+</sup>
NKG2C<sup>+</sup>
T cells against HIV‐infected CD4 T cells</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Garrido <italic>et al</italic>
. 2018<xref rid="cti21072-bib-0100" ref-type="ref">100</xref>
</td>
<td align="left" rowspan="1" colspan="1">HIV</td>
<td align="left" rowspan="1" colspan="1">ART‐suppressed HIV‐infected adult men</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>+</sup>
T cells expanded up to 120‐fold in response to PAM/IL‐2 <italic>ex vivo</italic>
</td>
<td align="left" rowspan="1" colspan="1">γδ T cells are capable of eliminating HIV‐infected targets and reduced viral replication up to 80%</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">He <italic>et al</italic>
. 2013<xref rid="cti21072-bib-0098" ref-type="ref">98</xref>
</td>
<td align="left" rowspan="1" colspan="1">HIV</td>
<td align="left" rowspan="1" colspan="1">HIV‐positive and HIV‐negative adults</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1">CD16‐ and CD16<sup>+</sup>
Vδ2<sup>+</sup>
T‐cell subsets performed different functions in response to various stimuli</td>
<td align="left" rowspan="1" colspan="1">Potential for CD16<sup>+</sup>
Vδ2<sup>+</sup>
cells to control HIV infection via antibody‐dependent cell‐mediated cytotoxicity</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Riedel <italic>et al</italic>
. 2009<xref rid="cti21072-bib-0091" ref-type="ref">91</xref>
</td>
<td align="left" rowspan="1" colspan="1">HIV</td>
<td align="left" rowspan="1" colspan="1">HIV‐1‐infected adults that are natural viral suppressors (NVS)</td>
<td align="left" rowspan="1" colspan="1">Vγ9Vδ2</td>
<td align="left" rowspan="1" colspan="1">Depletion of Vγ9Vδ2 T cells occurs early in HIV disease; NVS patients demonstrated an increased number of Vγ9Vδ2 T cells</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Wallace <italic>et al</italic>
. 1996<xref rid="cti21072-bib-0088" ref-type="ref">88</xref>
</td>
<td align="left" rowspan="1" colspan="1">HIV</td>
<td align="left" rowspan="1" colspan="1">Age not reported</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Increased numbers of γδ T cells in HIV‐1‐infected individuals</td>
<td align="left" rowspan="1" colspan="1">Anti‐HIV responses in a large proportion of Vγ9Vδ2 T cells may help explain the phenomenon of HIV exposure without infection</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Worku <italic>et al</italic>
. 2001<xref rid="cti21072-bib-0101" ref-type="ref">101</xref>
</td>
<td align="left" rowspan="1" colspan="1">Canarypox ALVAC‐HIV vCP205 and rgp120</td>
<td align="left" rowspan="1" colspan="1">Adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">Induction of γδ T cells specific for canarypox (not HIV) antigens following vaccination</td>
<td align="left" rowspan="1" colspan="1">Expanded Vγ9<sup>+</sup>
γδ T cells produce IFNγ</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Lafarge <italic>et al</italic>
. 2001<xref rid="cti21072-bib-0106" ref-type="ref">106</xref>
</td>
<td align="left" rowspan="1" colspan="1">Cytomegalovirus (CMV)</td>
<td align="left" rowspan="1" colspan="1">Renal transplant patients</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1"></td>
<td align="left" rowspan="1" colspan="1">Patients with γδ T‐cell expansion > 45 days after transplant had more severe symptoms than patients with early γδ T‐cell expansion; CMV infection resolves following γδ T‐cell expansion</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Halary <italic>et al</italic>
. 2005<xref rid="cti21072-bib-0108" ref-type="ref">108</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Renal‐ and lung‐transplanted patients with CMV</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
T cells express receptors involved in intestinal homing</td>
<td align="left" rowspan="1" colspan="1">Numerous Vδ1<sup>+</sup>
, Vδ3<sup>+</sup>
and Vδ5<sup>+</sup>
patient clones express TNFα, kill CMV‐infected targets and limit CMV growth <italic>in vitro</italic>
; high frequency of these cells induce CD107a expression in the presence of CMV‐infected cells</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Pitard <italic>et al</italic>
. 2008<xref rid="cti21072-bib-0102" ref-type="ref">102</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Renal transplant patients with CMV and healthy adult donors (CMV seropositive/seronegative)</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
T cells expand and show effector/memory phenotype in transplanted patients and CMV+ healthy donors</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
T cells from transplanted patients/CMV+ healthy donors show increased cytotoxicity in response to CMV <italic>in vitro</italic>
; secondary response to CMV associated with a faster γδ T‐cell expansion and better resolution of infection compared to primary response</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Knight <italic>et al</italic>
. 2010<xref rid="cti21072-bib-0107" ref-type="ref">107</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Allogeneic stem cell transplant patients and healthy adult donors (CMV+/‐)</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">Long‐term expansion of Vδ2<sup>−</sup>
(not Vδ2<sup>+</sup>
) T cells in transplant patients with CMV reactivation and in CMV+ healthy donors; restricted clonality</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
T cells from CMV+ healthy donors and from a recipient of a graft from a CMV+ donor lysed CMV‐infected cells <italic>in vitro</italic>
</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Couzi <italic>et al</italic>
. 2012<xref rid="cti21072-bib-0109" ref-type="ref">109</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Kidney transplant patients and healthy donors</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">High expression of CD16 on Vδ2<sup>−</sup>
T cells from CMV+ individuals</td>
<td align="left" rowspan="1" colspan="1">CD16<sup>+</sup>
γδ T cells did not mediate ADCC against CMV‐infected cells but produced IFNγ when incubated with IgG‐opsonised virions and inhibited CMV multiplication <italic>in vitro</italic>
</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Roux <italic>et al</italic>
. 2013<xref rid="cti21072-bib-0104" ref-type="ref">104</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Adults from various age groups, pregnant women with primary infection, lung‐transplanted patients with primary or chronic infection</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">CMV seropositivity leads to accumulation of highly differentiated Vδ2<sup>−</sup>
(but not Vδ2<sup>+</sup>
) T cells; highest CD38 expression on γδ T cells from individuals with primary infection compared to chronic infection or no infection</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Alejenef <italic>et al</italic>
. 2014<xref rid="cti21072-bib-0103" ref-type="ref">103</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Healthy adults and 2 immunocompromised individuals with symptomatic primary infection</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">Highly differentiated effector memory Vδ2<sup>−</sup>
γδ T cells significantly increased in CMV+ healthy individuals compared to CMV‐ controls in all age groups</td>
<td align="left" rowspan="1" colspan="1">Vδ2<sup>−</sup>
T cells from CMV+ individuals contained higher levels of intracellular perforin and granzyme than CMV‐ individuals; Vδ2<sup>−</sup>
T cells do not immediately produce IFNγ/TNFα/CD107a following <italic>ex vivo</italic>
incubation with CMV‐infected cells but do demonstrate effector functions after short‐term culture</td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Kallemeijn <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0113" ref-type="ref">113</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Healthy adults</td>
<td align="left" rowspan="1" colspan="1">All γδ</td>
<td align="left" rowspan="1" colspan="1">CMV associated with higher frequencies of γδ T cells with effector/memory and exhausted phenotypes</td>
<td align="left" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Lee <italic>et al</italic>
. 2017<xref rid="cti21072-bib-0105" ref-type="ref">105</xref>
</td>
<td align="left" rowspan="1" colspan="1">CMV</td>
<td align="left" rowspan="1" colspan="1">Renal transplant patients several years post‐transplant and healthy donors</td>
<td align="left" rowspan="1" colspan="1">All γδ/Vδ2<sup>−</sup>
</td>
<td align="left" rowspan="1" colspan="1">Percentages of Vδ2<sup>−</sup>
T cells higher in CMV+ transplant patients and correlated with CMV antibody levels; Vδ2<sup>−</sup>
T cells skewed towards terminally differentiated phenotype; many Vδ2<sup>−</sup>
T cells in CMV+ individuals express CD8</td>
<td align="left" rowspan="1" colspan="1">Expression of CD107a and production of IFNγ by Vδ2<sup>+</sup>
and Vδ2− γδ T cells in response to staphylococcal enterotoxin B was not altered by CMV</td>
</tr>
</tbody>
</table>
<permissions><copyright-holder>John Wiley & Sons, Ltd</copyright-holder>
</permissions>
</table-wrap>
<p>To maximise functional responses in future similar studies, it will be important to improve our understanding of the timing of γδ T‐cell <italic>vs</italic>
. αβ T‐cell responses following vaccination, as well as any potential negative effects of overstimulation of γδ T cells. As specific subsets of γδ T cells that correlate with protection in different contexts are identified, optimisation of methods to specifically target these subsets will be beneficial. Especially given the hypothetical possibility of γδ T‐cell anergy/exhaustion, it will be essential to define responses that optimally stimulate and antigens/agonists that best elicit that response. Altogether, as development of vaccines targeting infectious diseases that have long proved elusive becomes more of a reality, it will be important to broaden our perspective beyond targeting antibody‐driven or T‐cell responses and to intentionally target innate cells, such as γδ T cells.</p>
</sec>
<sec sec-type="COI-statement" id="cti21072-sec-0007"><title>Conflict of interest</title>
<p>The authors declare no conflict of interest.</p>
</sec>
</body>
<back><ack id="cti21072-sec-0006"><title>Acknowledgments</title>
<p>This work was supported in part by AI 118610 (pilot project grant to PJ).</p>
</ack>
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