Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
Identifieur interne : 000925 ( Pmc/Curation ); précédent : 000924; suivant : 000926Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths
Auteurs : K A Smith [Royaume-Uni] ; K J Filbey [Royaume-Uni] ; L A Reynolds [Royaume-Uni] ; J P Hewitson [Royaume-Uni] ; Y. Harcus [Royaume-Uni] ; L. Boon [Pays-Bas] ; T. Sparwasser [Allemagne] ; G. H Mmerling [Allemagne] ; R M Maizels [Royaume-Uni]Source :
- Mucosal Immunology [ 1933-0219 ] ; 2015.
Abstract
Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth
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DOI: 10.1038/mi.2015.73
PubMed: 26286232
PubMed Central: 4677460
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths</title><author><name sortKey="Smith, K A" sort="Smith, K A" uniqKey="Smith K" first="K A" last="Smith">K A Smith</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Filbey, K J" sort="Filbey, K J" uniqKey="Filbey K" first="K J" last="Filbey">K J Filbey</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reynolds, L A" sort="Reynolds, L A" uniqKey="Reynolds L" first="L A" last="Reynolds">L A Reynolds</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hewitson, J P" sort="Hewitson, J P" uniqKey="Hewitson J" first="J P" last="Hewitson">J P Hewitson</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Harcus, Y" sort="Harcus, Y" uniqKey="Harcus Y" first="Y" last="Harcus">Y. Harcus</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boon, L" sort="Boon, L" uniqKey="Boon L" first="L" last="Boon">L. Boon</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Bioceros Holding BV</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sparwasser, T" sort="Sparwasser, T" uniqKey="Sparwasser T" first="T" last="Sparwasser">T. Sparwasser</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>TwinCore</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="H Mmerling, G" sort="H Mmerling, G" uniqKey="H Mmerling G" first="G" last="H Mmerling">G. H Mmerling</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Division of Molecular Immunology, German Cancer Research Center</institution>, Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Maizels, R M" sort="Maizels, R M" uniqKey="Maizels R" first="R M" last="Maizels">R M Maizels</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26286232</idno><idno type="pmc">4677460</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677460</idno><idno type="RBID">PMC:4677460</idno><idno type="doi">10.1038/mi.2015.73</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000925</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000925</idno><idno type="wicri:Area/Pmc/Curation">000925</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000925</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths</title><author><name sortKey="Smith, K A" sort="Smith, K A" uniqKey="Smith K" first="K A" last="Smith">K A Smith</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Filbey, K J" sort="Filbey, K J" uniqKey="Filbey K" first="K J" last="Filbey">K J Filbey</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reynolds, L A" sort="Reynolds, L A" uniqKey="Reynolds L" first="L A" last="Reynolds">L A Reynolds</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hewitson, J P" sort="Hewitson, J P" uniqKey="Hewitson J" first="J P" last="Hewitson">J P Hewitson</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Harcus, Y" sort="Harcus, Y" uniqKey="Harcus Y" first="Y" last="Harcus">Y. Harcus</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boon, L" sort="Boon, L" uniqKey="Boon L" first="L" last="Boon">L. Boon</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Bioceros Holding BV</institution>, Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sparwasser, T" sort="Sparwasser, T" uniqKey="Sparwasser T" first="T" last="Sparwasser">T. Sparwasser</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>TwinCore</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="H Mmerling, G" sort="H Mmerling, G" uniqKey="H Mmerling G" first="G" last="H Mmerling">G. H Mmerling</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Division of Molecular Immunology, German Cancer Research Center</institution>, Heidelberg,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Maizels, R M" sort="Maizels, R M" uniqKey="Maizels R" first="R M" last="Maizels">R M Maizels</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Mucosal Immunology</title><idno type="ISSN">1933-0219</idno><idno type="eISSN">1935-3456</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth <italic>Heligmosomoides polygyrus</italic> drives rapid polyclonal expansion of Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3<sup>+</sup>Helios<sup>−</sup>CD4<sup>+</sup> peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> tTreg numbers. Boosting of Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness <italic>in vivo</italic>, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with “immunological chaos” evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody–mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mucosal Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Mucosal Immunol</journal-id><journal-title-group><journal-title>Mucosal Immunology</journal-title></journal-title-group><issn pub-type="ppub">1933-0219</issn><issn pub-type="epub">1935-3456</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26286232</article-id><article-id pub-id-type="pmc">4677460</article-id><article-id pub-id-type="pii">mi201573</article-id><article-id pub-id-type="doi">10.1038/mi.2015.73</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Smith</surname><given-names>K A</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>5</sup></xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><contrib contrib-type="author"><name><surname>Filbey</surname><given-names>K J</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Reynolds</surname><given-names>L A</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hewitson</surname><given-names>J P</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Harcus</surname><given-names>Y</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Boon</surname><given-names>L</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sparwasser</surname><given-names>T</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hämmerling</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Maizels</surname><given-names>R M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf2">*</xref></contrib><aff id="aff1"><label>1</label><institution>Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, University of Edinburgh</institution>, Edinburgh,<country>UK</country></aff><aff id="aff2"><label>2</label><institution>Bioceros Holding BV</institution>, Utrecht,<country>The Netherlands</country></aff><aff id="aff3"><label>3</label><institution>TwinCore</institution>, Hannover,<country>Germany</country></aff><aff id="aff4"><label>4</label><institution>Division of Molecular Immunology, German Cancer Research Center</institution>, Heidelberg,<country>Germany</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><email>r.maizels@ed.ac.uk</email></corresp><corresp id="caf2"><label>*</label><email>smithk28@cardiff.ac.uk</email></corresp><fn fn-type="present-address" id="note1"><label>5</label><p>Current address: Institute of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.</p></fn></author-notes><pub-date pub-type="ppub"><month>03</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>19</day><month>08</month><year>2015</year></pub-date><volume>9</volume><issue>2</issue><fpage>428</fpage><lpage>443</lpage><history><date date-type="received"><day>07</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>26</day><month>06</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2016 Society for Mucosal Immunology</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Society for Mucosal Immunology</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth <italic>Heligmosomoides polygyrus</italic> drives rapid polyclonal expansion of Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3<sup>+</sup>Helios<sup>−</sup>CD4<sup>+</sup> peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> tTreg numbers. Boosting of Foxp3<sup>+</sup>Helios<sup>+</sup>CD4<sup>+</sup> tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness <italic>in vivo</italic>, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with “immunological chaos” evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody–mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency.</p></abstract></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Differential susceptibility to infection and generation of thymic regulatory T cells (tTregs). (<bold>a</bold>) Female BALB/c and C57BL/6 mice were infected with 200 L3 stage <italic>H. polygyrus</italic> and adult egg counts were quantified at day 28 postinfection. Single-cell suspensions of mesenteric lymph node were analyzed in naive (white symbols) and day-28 infected (black symbols) mice for the proportion of CD4<sup>+</sup> T cells expressing (<bold>b</bold>) Foxp3 and (<bold>c</bold>) the percentage of CD4<sup>+</sup>Foxp3<sup>+</sup> T cells expressing CD103 by flow cytometry. (<bold>d</bold>, <bold>e</bold>) The total numbers of CD4<sup>+</sup>Foxp3<sup>+</sup> tTregs (Helios<sup>+</sup>) and peripheral Tregs (Helios<sup>−</sup>) were determined in the two strains. (<bold>f</bold>, <bold>g</bold>) Significant positive correlations between adult worm burdens and total numbers of tTregs and CD103<sup>+</sup> tTregs were found in BALB/c mice; <italic>r</italic>=Spearman <italic>r</italic> value. Data shown include totals of 10 naive and 40 infected mice of each strain, as previously detailed.<sup><xref ref-type="bibr" rid="bib31">31</xref></sup></p></caption><graphic xlink:href="mi201573f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Expansion of Foxp3<sup>+</sup> regulatory T cells (Tregs) in mesenteric lymph node (MLN) and lamina propria (LP) following <italic>H. polygyrus</italic> infection. (<bold>a</bold>) Female BALB/c mice were naive or infected with 200 L3 stage <italic>H. polygyrus</italic> and single-cell suspensions of (<bold>a</bold> and <bold>b</bold>, left) MLN and (<bold>a</bold> and <bold>b</bold>, right) LP were analyzed by flow cytometry at day 5 postinfection for the proportion and number of Foxp3<sup>+</sup>CD4<sup>+</sup> Treg and the proportion of Foxp3<sup>+</sup>CD4<sup>+</sup>Helios<sup>+</sup> thymic Treg and Foxp3<sup>+</sup>CD4<sup>+</sup>Helios<sup>−</sup> peripheral Treg. (<bold>b</bold>) Proliferation within CD4<sup>+</sup>Foxp3<sup>−</sup> T-cell and CD4<sup>+</sup>Foxp3<sup>+</sup> Treg compartments was measured using Ki67<sup>+</sup>. Cells were gated on live, CD4<sup>+</sup> T cells; fold proliferation was calculated using: mean percentage of Ki67 from infected mice/mean percentage of Ki67 from naive mice. (<bold>c</bold>) T-cell receptor Vβ expression was quantified by flow cytometry within CD4<sup>+</sup>Foxp3<sup>+</sup> (left) and CD4<sup>+</sup>Foxp3<sup>+</sup>CD103<sup>+</sup> (right) T cells in naive and day-7 <italic>H. polygyrus</italic>–infected mice. Experiments shown are representative of two experiments with <italic>n</italic>⩾4 mice/group (<bold>a</bold>–<bold>c</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Boosting regulatory T cell (Treg) populations <italic>in vivo</italic> reduces parasite immunity in more resistant BALB/c mice. Naive BALB/c mice were treated with a complex of 2.5 μg recombinant interleukin-2 (rIL-2) and 25 μg anti-IL-2 (IL-2C) or 25 μg rat IgG2a isotype control (ISO) immediately before infection with 200 <italic>H. polygyrus</italic> by gavage. Mice were harvested at day 7 postinfection, and single-cell suspensions of mesenteric lymph node (MLN) were analyzed for (<bold>a</bold>) Foxp3<sup>+</sup> proportion and (<bold>b</bold>) Foxp3 number, as well as (<bold>c</bold>) thymic Treg and (<bold>d</bold>) peripheral Treg proportions within CD4<sup>+</sup> cells by flow cytometry. (<bold>e</bold>) Fecal egg burden was determined at day 14 and (<bold>f</bold>) adult worm burden enumerated at day 28 postinfection. MLN from day 7 postinfection were also analyzed for (<bold>g</bold>) the percentage of proliferating (Ki67<sup>+</sup>) effector CD4<sup>+</sup> T cells or plated and re-stimulated with 1 μg <italic>H. polygyrus</italic> excretory/secretory antigen (HES), anti-CD3, or media for 72 h and production of (<bold>h</bold>) IL-10, (<bold>i</bold>) IL-13, (<bold>j</bold>) IL-4, and (<bold>k</bold>) interferon (IFN)-γ in the supernatant was assessed by enzyme-linked immunosorbent assay. Intracellular straining of ionomycin and phorbol myristate acetate–stimulated CD4<sup>+</sup> T cells for (<bold>l</bold>) IL-13 and (<bold>m</bold>) IL-4 of the MLN was also performed. Experiments shown are one representative of two experiments with <italic>n</italic>⩾4 mice/group (<bold>a</bold>–<bold>d</bold> and <bold>g</bold>–<bold>m</bold>) or are pooled data from two experiments with <italic>n</italic>⩾4 mice/group (<bold>e</bold>, <bold>f</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Boosting regulatory T cell populations <italic>in vivo</italic> modifies innate type-2 immunity following <italic>H. polygyrus</italic> infection. Naive BALB/c mice were treated with a complex of 2.5 μg recombinant interleukin-2 (rIL-2) and 25 μg anti-IL-2 (IL-2C) or 25 μg rat IgG2a isotype control (ISO) immediately before infection with 200 <italic>H. polygyrus</italic> by gavage. (<bold>a</bold>) The number of CD3<sup>−</sup>CD4<sup>−</sup>CD8<sup>−</sup>CD5<sup>−</sup>CD11c<sup>−</sup>CD49b<sup>−</sup>F4/80<sup>−</sup> (Lin)<sup>−</sup>ICOS<sup>+</sup> innate lymphoid cells (ILCs) expressing (<bold>b</bold>) IL-5, (<bold>c</bold>) IL-13, and (<bold>d</bold>) IL-4 within the mesenteric lymph node (MLN) was also determined at day 7 postinfection by flow cytometry. (<bold>e</bold>) Intestinal granuloma formation was enumerated at day 28 postinfection. The production of the alternative activation markers RELM-α and Ym-1 within (<bold>f</bold>–<bold>i</bold>) the gut homogenate peritoneal lavage (PL) and (<bold>j</bold>) the proportion of macrophages (F4/80<sup>+</sup> within CD11b<sup>+</sup>Siglec-F<sup>−</sup>) and (<bold>k</bold>) macrophage proliferation (Ki67<sup>+</sup>) within the PL was determined by enzyme-linked immunosorbent assay and flow cytometry at day 7 postinfection. Experiments shown are one representative of two experiments with <italic>n</italic>⩾4 mice/group (<bold>a</bold>–<bold>d</bold> and <bold>f</bold>–<bold>k</bold>) or are pooled data from two experiments with <italic>n</italic>⩾4 mice/group (<bold>e</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Early depletion of regulatory T cell (Treg) populations <italic>in vivo</italic> transgenic BALB/c Foxp3.LuciDTR mice. (<bold>a</bold>) BALB/c Foxp3.LuciDTR mice were treated with 24 ng g<sup>−1</sup> diphtheria toxin (DTx) following infection with 200 <italic>H. polygyrus</italic> by gavage. The proportion of (<bold>b</bold>) Foxp3GFP<sup>+</sup> Treg and (<bold>c</bold>) CD4<sup>+</sup>Foxp3<sup>+</sup> Treg within the mesenteric lymph node (MLN) of DTx-treated day 7 <italic>H. polygyrus</italic>–infected transgene negative (−ive) and positive (+ive) mice was determined by flow cytometry. (<bold>d</bold>) Fecal parasite egg counts were determined at day 14 postinfection and (<bold>e</bold>) intestinal adult worm burden enumerated at day 28 postinfection in <italic>H. polygyrus</italic> in Treg-replete and -depleted mice. MLN from day 7 postinfection were re-stimulated with 1 μg <italic>H. polygyrus</italic> excretory/secretory antigen (HES) or media for 72 h and production of antigen-specific (<bold>f</bold>) interleukin (IL)-4, (<bold>g</bold>) interferon (IFN)-γ, and (<bold>h</bold>) IL-6 in the supernatant was assessed by enzyme-linked immunosorbent assay (ELISA). BALB/c Foxp3.LuciDTR mice were subsequently treated with 0.5 mg anti-IFN-γ or rat IgG1 isotype control (ISO) intraperitoneally on days 2, 4, and 6 postinfection in addition to DTx treatment. (<bold>i</bold>) MLN from day 7 postinfection were re-stimulated with 1 μg HES or media for 72 h and production of antigen-specific IFN-γ in the supernatant was assessed by ELISA. (<bold>j</bold>) Intestinal parasite worm burdens were enumerated at day 28 postinfection in Treg-depleted mice treated with neutralizing IFN-γ antibody or an isotype control. MLN production of (<bold>k</bold>) IL-4 and (<bold>l</bold>) IL-6 in response to HES was measured in the same conditions described for IFN-γ. (<bold>m</bold>) The number of intestinal granulomas was enumerated at day 28 postinfection. (<bold>n</bold>) Survival of <italic>H. polygrus</italic>–infected transgene negative (−ive) and positive (+ive) mice was recorded. Experiments shown are one representative of two experiments with <italic>n</italic>⩾3 mice/group (<bold>b</bold>, <bold>c</bold>, <bold>f</bold>–<bold>i</bold>, <bold>k</bold>, <bold>l</bold>, <bold>n</bold>) or are pooled data fromtwo experiments with <italic>n</italic>⩾4 mice/group (<bold>d</bold>, <bold>e</bold>, <bold>m</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Late depletion of regulatory T cell (Treg) in more susceptible transgenic C57BL/6 Foxp3.LuciDTR mice does not alter parasite immunity. (<bold>a</bold>) C57BL/6 Foxp3.LuciDTR mice were treated with 24 ng g<sup>−1</sup> diphtheria toxin (DTx) intraperitoneally on days 14, 16, 18, 20, 22, 24, and 26 following infection with 200 <italic>H. polygyrus</italic> by gavage. At day 28 postinfection, the proportion of (<bold>b</bold>) CD4<sup>+</sup>Foxp3GFP<sup>+</sup> and (<bold>c</bold>) CD4<sup>+</sup>Foxp3<sup>+</sup> Treg within the mesenteric lymph node (MLN) of Treg-sufficient and -depleted mice was determined by flow cytometry. MLN cells were re-stimulated with 1 μg <italic>H. polygyrus</italic> excretory/secretory antigen (HES) or media for 72 h and production of antigen-specific (<bold>d</bold>) interleukin (IL)-4, (<bold>e</bold>) IL-10, and (<bold>f</bold>) interferon (IFN)-γ assessed in supernatants by enzyme-linked immunosorbent assay. (<bold>g</bold>) Fecal parasite egg was determined at day 14 postinfection and (<bold>h</bold>) intestinal adult worm burden enumerated at day 28 postinfection in <italic>H. polygyrus</italic> in Treg-replete (Hp:PBS (phosphate-buffered saline)) and Treg-depleted (Hp:DTx) mice. (<bold>i</bold>) Body weight of Treg-replete (Hp:PBS) and Treg-depleted (Hp:DTx) mice was recorded over time following <italic>H. polygyrus</italic> infection as a percentage of starting weight. Experiments shown are one representative of two experiments with <italic>n</italic>⩾4 mice/group (<bold>b</bold>–<bold>e</bold>, <bold>g</bold>, <bold>i</bold>) or are pooled data from two experiments with <italic>n</italic>⩾4 mice/group (<bold>h</bold>) or three experiments with <italic>n</italic>⩾4 mice/group (<bold>f</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Antibody depletion of regulatory T cell (Treg) populations <italic>in vivo</italic> using anti-CD25 (PC61) increases parasite immunity in more resistant BALB/c mice. Naive BALB/c mice were treated with 1 mg anti-CD25 (clone PC-61) or rat IgG control (ISO) immediately before infection with 200 <italic>H. polgyrus</italic> by gavage. Mice were harvested at day 7 postinfection and single-cell suspensions of (<bold>a</bold>) blood and (<bold>b</bold>–<bold>d</bold>) mesenteric lymph node (MLN) analyzed for the proportion and proliferation (Ki67<sup>+</sup>) of CD4<sup>+</sup>Foxp3<sup>+</sup> Treg and CD4<sup>+</sup>Foxp3<sup>−</sup> T cells by flow cytometry. (<bold>e</bold>–<bold>g</bold>) MLN cells from day 7 postinfection were plated and re-stimulated with 1 μg <italic>H. polygyrus</italic> excretory/secretory antigen (HES), anti-CD3, or media for 72 h and production of interleukin (IL)-4, IL-13, and interferon (IFN)-γ in the supernatant was assessed by enzyme-linked immunosorbent assay. Intestinal adult worm burden was enumerated at (<bold>h</bold>) day 21 and (<bold>i</bold>) day 28 postinfection. (<bold>j</bold>) The number of intestinal granulomas was also enumerated at day 28 postinfection. (<bold>k</bold>) Macrophage proliferation (Ki67<sup>+</sup>) within the peritoneal lavage (PL) was determined by flow cytometry at day 7 postinfection and the production of the alternative activation markers (<bold>l</bold>) RELM-α and (<bold>m</bold>) Ym-1 within the gut homogenate determined at day 28 postinfection. Experiments shown are one representative of two experiments with <italic>n</italic>⩾4 mice/group (<bold>a</bold>–<bold>c</bold>, <bold>e</bold>, <bold>f</bold>, <bold>k</bold>–<bold>m</bold>) or are pooled data from two experiments with <italic>n</italic>⩾4 mice/group (<bold>d</bold>, <bold>g</bold>–<bold>j</bold>). NS, not significant.</p></caption><graphic xlink:href="mi201573f7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>Schematic summarizing the role of regulatory T cell (Treg) in controlling pathology and inflammatory responses following <italic>H. polygyrus</italic> infection. Left: In <italic>H. polygyrus</italic> infection of mice, an absence of Treg results in uncontrolled T helper type 1 (Th1) responses and increased parasite persistence and pathology, without affecting Th2 development (e.g., in DEREG and Fop3.LuciDTR mice). Center: A low level of Treg controls excessive Th1 responses but allows Th2 responses to dominate resulting in adult worm clearance (e.g., anti-CD25 treatment). Right of the panel: A high level of Tregs (e.g., following administration of recombinant interleukin-2 (rIL-2):anti-IL-2) suppresses both Th1 and Th2 responses, increasing parasite survival and resulting in suppression of immunity to bystander antigens.</p></caption><graphic xlink:href="mi201573f8"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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