DOCK8 Drives Src-Dependent NK Cell Effector Function.
Identifieur interne : 000E78 ( Main/Exploration ); précédent : 000E77; suivant : 000E79DOCK8 Drives Src-Dependent NK Cell Effector Function.
Auteurs : Conor J. Kearney [Australie] ; Stephin J. Vervoort [Australie] ; Kelly M. Ramsbottom [Australie] ; Andrew J. Freeman [Australie] ; Jessica Michie [Australie] ; Jane Peake [Australie] ; Jean-Laurent Casanova [France] ; Capucine Picard [France] ; Stuart G. Tangye [Australie] ; Cindy S. Ma [Australie] ; Ricky W. Johnstone [Australie] ; Katrina L. Randall ; Jane OliaroSource :
- Journal of immunology (Baltimore, Md. : 1950) [ 1550-6606 ] ; 2017.
Abstract
Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.
DOI: 10.4049/jimmunol.1700751
PubMed: 28794229
Affiliations:
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Kearney</name><affiliation wicri:level="1"><nlm:affiliation>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000</wicri:regionArea><wicri:noRegion>Victoria 3000</wicri:noRegion></affiliation></author><author><name sortKey="Vervoort, Stephin J" sort="Vervoort, Stephin J" uniqKey="Vervoort S" first="Stephin J" last="Vervoort">Stephin J. Vervoort</name><affiliation wicri:level="1"><nlm:affiliation>Gene Regulation Laboratory, Cancer Therapeutics Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Gene Regulation Laboratory, Cancer Therapeutics Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000</wicri:regionArea><wicri:noRegion>Victoria 3000</wicri:noRegion></affiliation></author><author><name sortKey="Ramsbottom, Kelly M" sort="Ramsbottom, Kelly M" uniqKey="Ramsbottom K" first="Kelly M" last="Ramsbottom">Kelly M. Ramsbottom</name><affiliation wicri:level="1"><nlm:affiliation>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000</wicri:regionArea><wicri:noRegion>Victoria 3000</wicri:noRegion></affiliation></author><author><name sortKey="Freeman, Andrew J" sort="Freeman, Andrew J" uniqKey="Freeman A" first="Andrew J" last="Freeman">Andrew J. Freeman</name><affiliation wicri:level="1"><nlm:affiliation>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000</wicri:regionArea><wicri:noRegion>Victoria 3000</wicri:noRegion></affiliation></author><author><name sortKey="Michie, Jessica" sort="Michie, Jessica" uniqKey="Michie J" first="Jessica" last="Michie">Jessica Michie</name><affiliation wicri:level="1"><nlm:affiliation>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000</wicri:regionArea><wicri:noRegion>Victoria 3000</wicri:noRegion></affiliation></author><author><name sortKey="Peake, Jane" sort="Peake, Jane" uniqKey="Peake J" first="Jane" last="Peake">Jane Peake</name><affiliation wicri:level="1"><nlm:affiliation>University of Queensland and Lady Cilento Children's Hospital, Brisbane, Queensland 4006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>University of Queensland and Lady Cilento Children's Hospital, Brisbane, Queensland 4006</wicri:regionArea><wicri:noRegion>Queensland 4006</wicri:noRegion></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Medical School, University Paris Descartes, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Medical School, University Paris Descartes, 75015 Paris</wicri:regionArea><wicri:noRegion>75015 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Medical School, University Paris Descartes, 75015 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Medical School, University Paris Descartes, 75015 Paris</wicri:regionArea><wicri:noRegion>75015 Paris</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Tangye, Stuart G" sort="Tangye, Stuart G" uniqKey="Tangye S" first="Stuart G" last="Tangye">Stuart G. Tangye</name><affiliation wicri:level="1"><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010</wicri:regionArea><wicri:noRegion>New South Wales 2010</wicri:noRegion></affiliation></author><author><name sortKey="Ma, Cindy S" sort="Ma, Cindy S" uniqKey="Ma C" first="Cindy S" last="Ma">Cindy S. Ma</name><affiliation wicri:level="1"><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010</wicri:regionArea><wicri:noRegion>New South Wales 2010</wicri:noRegion></affiliation></author><author><name sortKey="Johnstone, Ricky W" sort="Johnstone, Ricky W" uniqKey="Johnstone R" first="Ricky W" last="Johnstone">Ricky W. Johnstone</name><affiliation wicri:level="4"><nlm:affiliation>Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3052, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3052</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Randall, Katrina L" sort="Randall, Katrina L" uniqKey="Randall K" first="Katrina L" last="Randall">Katrina L. Randall</name><affiliation><nlm:affiliation>Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory 2601, Australia; and.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation></author><author><name sortKey="Oliaro, Jane" sort="Oliaro, Jane" uniqKey="Oliaro J" first="Jane" last="Oliaro">Jane Oliaro</name><affiliation><nlm:affiliation>Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; jane.oliaro@petermac.org.</nlm:affiliation><wicri:noCountry code="subField">Australia; jane.oliaro@petermac.org.</wicri:noCountry></affiliation></author></analytic><series><title level="j">Journal of immunology (Baltimore, Md. : 1950)</title><idno type="eISSN">1550-6606</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Victoria (État)</li><li>Île-de-France</li></region><settlement><li>Melbourne</li><li>Paris</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><noCountry><name sortKey="Oliaro, Jane" sort="Oliaro, Jane" uniqKey="Oliaro J" first="Jane" last="Oliaro">Jane Oliaro</name><name sortKey="Randall, Katrina L" sort="Randall, Katrina L" uniqKey="Randall K" first="Katrina L" last="Randall">Katrina L. Randall</name></noCountry><country name="Australie"><noRegion><name sortKey="Kearney, Conor J" sort="Kearney, Conor J" uniqKey="Kearney C" first="Conor J" last="Kearney">Conor J. Kearney</name></noRegion><name sortKey="Freeman, Andrew J" sort="Freeman, Andrew J" uniqKey="Freeman A" first="Andrew J" last="Freeman">Andrew J. Freeman</name><name sortKey="Johnstone, Ricky W" sort="Johnstone, Ricky W" uniqKey="Johnstone R" first="Ricky W" last="Johnstone">Ricky W. Johnstone</name><name sortKey="Ma, Cindy S" sort="Ma, Cindy S" uniqKey="Ma C" first="Cindy S" last="Ma">Cindy S. Ma</name><name sortKey="Michie, Jessica" sort="Michie, Jessica" uniqKey="Michie J" first="Jessica" last="Michie">Jessica Michie</name><name sortKey="Peake, Jane" sort="Peake, Jane" uniqKey="Peake J" first="Jane" last="Peake">Jane Peake</name><name sortKey="Ramsbottom, Kelly M" sort="Ramsbottom, Kelly M" uniqKey="Ramsbottom K" first="Kelly M" last="Ramsbottom">Kelly M. Ramsbottom</name><name sortKey="Tangye, Stuart G" sort="Tangye, Stuart G" uniqKey="Tangye S" first="Stuart G" last="Tangye">Stuart G. Tangye</name><name sortKey="Vervoort, Stephin J" sort="Vervoort, Stephin J" uniqKey="Vervoort S" first="Stephin J" last="Vervoort">Stephin J. Vervoort</name></country><country name="France"><region name="Île-de-France"><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name></region><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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