High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept

The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation, which led us to investigate the etiology of belatacept-resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cells that collectively enable protection against diverse classes of pathogens and can cross-react with allogeneic antigen and mediate graft rejection. T helper 17 (Th17) cells are a pro-inflammatory CD4⁺ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1) and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation. Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4 ⁺ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies. This study demonstrates that human Th17 cells are resistant to the costimulation inhibitor belatacept and that a high frequency of Th17 memory cells is associated with acute rejection episodes in belatacept-treated renal transplant recipients.