Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept‐Resistant Rejection in Human Renal Transplant Recipients

While most human T cells express the CD28 costimulatory molecule constitutively, it is well known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade‐resistant rejection. However, CD28+ cells possess more proliferative and multifunctional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those who did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept‐based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL‐2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept‐treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pretransplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept. A retrospective immunophenotypic analysis of adult renal transplant recipients demonstrates that patients who experience acute rejection on belatacept possess higher pretransplant frequencies of CD28+ CD4+ T than those who are stable on belatacept. See the companion article from Mathews et al on page 2285 and the editorial from Wekerle on page 2235.