Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells

Recently newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent is associated with superior patient survival and graft function than traditional therapy but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely employed. To that end we designed a study in a non-human primate kidney transplant model where animals were treated with either a belatacept- or a tacrolimus-based immunosuppressive regimen. Interestingly we found that elevated pre-transplant frequencies of CD28+CD8+TEMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28+CD8+TEMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28-. These data suggest that CD28+ memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28+ memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation independent rejection. This article is protected by copyright. All rights reserved.