Investigating The Functional Role of CD28 On Belatacept-Resistant Human TH17 Memory Cells.: Abstract# B1134

Pathogen primed memory T cells can cross-react with allogeneic antigen and mediate graft rejection, a process termed allogeneic heterologous immunity. Heterologous T cell responses have been directly demonstrated to be a barrier to tolerance induction strategies such as costimulation blockade, highlighting the importance of understanding phenotypic diversity among pathogen elicited T cell subsets. The CD28/CTLA-4 costimulation blocker belatacept 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. Th17 cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that Th17 memory cells are uniquely resistant to belatacept and associated with acute rejection in renal transplant recipients, but the mechanism of this resistance remains unclear. Our data demonstrate that CD4+ Th1 and Th17 memory cell subsets constitutively express the costimulatory receptor CD28, leading us to investigate whether Th17 cells are sensitive to selective CD28 blockade with domain antibodies (dAbs) that leave coinhibitory CTLA-4 signaling intact. Selective CD28 blockade inhibited Th1 cells but surprisingly augmented Th17 responses. Conversely, CD28 ligation inhibited Th17 populations. Following CD28 agonism, Th17 memory cells similarly upregulated the activation marker CD69 but expressed significantly greater amounts of coinhibitory CTLA-4 compared to Th1 cells. Relative to Th1 cells, Th17 cells also expressed lower levels of the transcription factors FOXO1 and FOXO3, which bind upstream of the CTLA-4 gene, suggesting a repressive role for these molecules in the expression of CTLA-4. These results demonstrate that the CD28 receptor has distinct functions on Th1 vs. Th17 memory cells and suggest novel mechanisms of costimulation on Th17 memory cells. Thus, this study has identified differences in costimulatory pathways of CD4+ memory subsets, and demonstrates that the heterogeneity of pathogen-derived memory has implications for the immunomodulation of pathologic T cell responses. DISCLOSURES:Suchard, S.: Employee, Bristol-Meyers Squibb. Nadler, S.: Employee, Bristol-Meyers Squibb.