Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure.

BACKGROUND: 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. METHODS: We investigated the frequency and function of CD8(+) T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8(+) T cells-in 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(+) T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. RESULTS: Increased frequency of circulating TEMRA CD8(+) 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(+) T cells associated with reduced risk of graft failure. A distinct TEMRA CD8(+) T cell subpopulation was identified that was characterized by expression of FcgammaRIIIA (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(+) T cells, CD16 engagement resulted in selective activation of TEMRA CD8(+) T cells, which mediated antibody-dependent cytotoxicity. CONCLUSIONS: At 1 year post-transplant, the composition of memory CD8(+) 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(+) 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(+) T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8(+) T cell monitoring for predicting risk of kidney transplant failure.