Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure
Authors: Lola Jacquemont, Gaëlle Tilly, Michelle Yap, Tra-My Doan-Ngoc, Richard Danger, Pierrick Guérif, Florent Delbos, Bernard Martinet, Magali Giral, Yohann Foucher, Sophie Brouard, Nicolas Degauque
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Identifying biomarkers for predicting kidney transplant failure requires better understanding of the immune response to chronic allogeneic stimulation. The authors demonstrated that 1 year after kidney transplantation, the composition of CD8 + memory T cell subsets in blood—specifically the ratio of terminally differentiated effector memory (TEMRA) and effector memory CD8 + T cells—is 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 + T cells display a novel T cell receptor–independent 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 + T cells in chronic humoral and cellular rejection leading to kidney transplant failure. Future clinical benefits may include the use of CD8 + memory T cell monitoring to improve risk prediction for graft failure and development of therapeutic strategies targeting TEMRA CD8 + T cells. 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 Fc γ 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 + 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.