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The authors demonstrated that 1 year after kidney transplantation, the composition of CD8\n                      <jats:sup>+<\/jats:sup>\n                      memory T cell subsets in blood\u2014specifically the ratio of terminally differentiated effector memory (TEMRA) and effector memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells\u2014is associated with risk for subsequent graft failure and adds predictive value to a previously reported eight-variable clinical risk score. They also found that TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells display a novel T cell receptor\u2013independent mechanism of activation that is mediated through CD16 engagement and results in inflammation and antibody-dependent cellular cytotoxicity. These findings suggest a pivotal role for TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in chronic humoral and cellular rejection leading to kidney transplant failure. Future clinical benefits may include the use of CD8\n                      <jats:sup>+<\/jats:sup>\n                      memory T cell monitoring to improve risk prediction for graft failure and development of therapeutic strategies targeting TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the frequency and function of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subsets\u2014including effector memory (EM) and terminally differentiated EM (TEMRA) CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells\u2014in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Increased frequency of circulating TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells associated with reduced risk of graft failure. A distinct TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subpopulation was identified that was characterized by expression of Fc\n                      <jats:italic toggle=\"yes\">\u03b3<\/jats:italic>\n                      RIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, CD16 engagement resulted in selective activation of TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, which mediated antibody-dependent cytotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      At 1 year post-transplant, the composition of memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell monitoring for predicting risk of kidney transplant failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2019080847","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T16:15:10Z","timestamp":1584029710000},"page":"876-891","source":"Crossref","is-referenced-by-count":80,"title":["Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure"],"prefix":"10.1681","volume":"31","author":[{"given":"Lola","family":"Jacquemont","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;"},{"name":"CHU Nantes, Universit\u00e9 de Nantes, ITUN, Nantes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Tilly","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;"},{"name":"CHU Nantes, Universit\u00e9 de Nantes, ITUN, Nantes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Yap","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;"},{"name":"CHU Nantes, Universit\u00e9 de Nantes, ITUN, Nantes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tra-My","family":"Doan-Ngoc","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Martinet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;"},{"name":"CHU Nantes, Universit\u00e9 de Nantes, ITUN, Nantes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Giral","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;"},{"name":"CHU Nantes, Universit\u00e9 de Nantes, ITUN, Nantes, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0330-7457","authenticated-orcid":false,"given":"Yohann","family":"Foucher","sequence":"additional","affiliation":[{"name":"INSERM, Universit\u00e9 de Nantes, methodS in Patient-centered outcomes and HEalth ResEarch (SPHERE), 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