Sestrins induce natural killer function in senescent-like CD8+ T cells

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 + T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27 − CD28 − CD8 + T cells...

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Veröffentlicht in:	Nature immunology 2020-06, Vol.21 (6), p.684-694
Hauptverfasser:	Pereira, Branca I., De Maeyer, Roel P. H., Covre, Luciana P., Nehar-Belaid, Djamel, Lanna, Alessio, Ward, Sophie, Marches, Radu, Chambers, Emma S., Gomes, Daniel C. O., Riddell, Natalie E., Maini, Mala K., Teixeira, Vitor H., Janes, Samuel M., Gilroy, Derek W., Larbi, Anis, Mabbott, Neil A., Ucar, Duygu, Kuchel, George A., Henson, Sian M., Strid, Jessica, Lee, Jun H., Banchereau, Jacques, Akbar, Arne N.
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Sprache:	eng
Schlagworte:	631/250/1619/554/1834 631/250/2152/1566 631/250/580/1884 Adaptor Proteins, Signal Transducing - metabolism Aging Biomedical and Life Sciences Biomedicine CD27 antigen CD28 antigen CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell differentiation Cellular Senescence - immunology Cytometry Cytotoxicity Cytotoxicity, Immunologic DAP12 protein Gene Expression Profiling Humans Immune system Immunology Immunoprecipitation Infectious Diseases Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Lymphocytes Lymphocytes T Membrane Proteins - metabolism Natural killer cells NK Cell Lectin-Like Receptor Subfamily K - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Receptors, Antigen, T-Cell - metabolism Receptors, Natural Killer Cell - metabolism Senescence Signal Transduction T cell receptors Yellow Fever - genetics Yellow Fever - immunology Yellow Fever - metabolism Yellow Fever - virology Yellow fever virus - immunology
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container_title	Nature immunology
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creator	Pereira, Branca I. De Maeyer, Roel P. H. Covre, Luciana P. Nehar-Belaid, Djamel Lanna, Alessio Ward, Sophie Marches, Radu Chambers, Emma S. Gomes, Daniel C. O. Riddell, Natalie E. Maini, Mala K. Teixeira, Vitor H. Janes, Samuel M. Gilroy, Derek W. Larbi, Anis Mabbott, Neil A. Ucar, Duygu Kuchel, George A. Henson, Sian M. Strid, Jessica Lee, Jun H. Banchereau, Jacques Akbar, Arne N.
description	Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 + T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27 − CD28 − CD8 + T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27 − CD28 − CD8 + T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27 − CD28 − CD8 + T cells to acquire a broad-spectrum, innate-like killing activity. Akbar and colleagues show that sestrins induce the reprogramming of non-proliferative, senescent-like CD27 – CD28 – CD8 + T cells to acquire an innate-like killing activity modulated by the NK receptor NKG2D and the adaptor molecule DAP12.
doi_str_mv	10.1038/s41590-020-0643-3
format	Article
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H.</au><au>Covre, Luciana P.</au><au>Nehar-Belaid, Djamel</au><au>Lanna, Alessio</au><au>Ward, Sophie</au><au>Marches, Radu</au><au>Chambers, Emma S.</au><au>Gomes, Daniel C. O.</au><au>Riddell, Natalie E.</au><au>Maini, Mala K.</au><au>Teixeira, Vitor H.</au><au>Janes, Samuel M.</au><au>Gilroy, Derek W.</au><au>Larbi, Anis</au><au>Mabbott, Neil A.</au><au>Ucar, Duygu</au><au>Kuchel, George A.</au><au>Henson, Sian M.</au><au>Strid, Jessica</au><au>Lee, Jun H.</au><au>Banchereau, Jacques</au><au>Akbar, Arne N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sestrins induce natural killer function in senescent-like CD8+ T cells</atitle><jtitle>Nature immunology</jtitle><stitle>Nat Immunol</stitle><addtitle>Nat Immunol</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>21</volume><issue>6</issue><spage>684</spage><epage>694</epage><pages>684-694</pages><issn>1529-2908</issn><eissn>1529-2916</eissn><abstract>Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 + T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27 − CD28 − CD8 + T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27 − CD28 − CD8 + T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27 − CD28 − CD8 + T cells to acquire a broad-spectrum, innate-like killing activity. Akbar and colleagues show that sestrins induce the reprogramming of non-proliferative, senescent-like CD27 – CD28 – CD8 + T cells to acquire an innate-like killing activity modulated by the NK receptor NKG2D and the adaptor molecule DAP12.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32231301</pmid><doi>10.1038/s41590-020-0643-3</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8387-7040</orcidid><orcidid>https://orcid.org/0000-0001-5877-0137</orcidid><orcidid>https://orcid.org/0000-0001-6002-5021</orcidid><orcidid>https://orcid.org/0000-0003-3535-7221</orcidid><orcidid>https://orcid.org/0000-0002-2200-6011</orcidid><orcidid>https://orcid.org/0000-0002-9772-3066</orcidid><orcidid>https://orcid.org/0000-0003-4041-0867</orcidid><orcidid>https://orcid.org/0000-0003-0090-861X</orcidid><orcidid>https://orcid.org/0000-0003-3476-0844</orcidid><orcidid>https://orcid.org/0000-0003-0990-8835</orcidid><orcidid>https://orcid.org/0000-0001-6384-1462</orcidid><orcidid>https://orcid.org/0000-0001-7395-1796</orcidid><orcidid>https://orcid.org/0000-0002-3763-9380</orcidid><orcidid>https://orcid.org/0000-0002-6634-5939</orcidid><orcidid>https://orcid.org/0000-0003-3690-2201</orcidid><oa>free_for_read</oa></addata></record>
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subjects	631/250/1619/554/1834 631/250/2152/1566 631/250/580/1884 Adaptor Proteins, Signal Transducing - metabolism Aging Biomedical and Life Sciences Biomedicine CD27 antigen CD28 antigen CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell differentiation Cellular Senescence - immunology Cytometry Cytotoxicity Cytotoxicity, Immunologic DAP12 protein Gene Expression Profiling Humans Immune system Immunology Immunoprecipitation Infectious Diseases Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Lymphocytes Lymphocytes T Membrane Proteins - metabolism Natural killer cells NK Cell Lectin-Like Receptor Subfamily K - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Receptors, Antigen, T-Cell - metabolism Receptors, Natural Killer Cell - metabolism Senescence Signal Transduction T cell receptors Yellow Fever - genetics Yellow Fever - immunology Yellow Fever - metabolism Yellow Fever - virology Yellow fever virus - immunology
title	Sestrins induce natural killer function in senescent-like CD8+ T cells
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