IFNγ production by donor-reactive memory CD4 T cells is required for CD40-independent induction of pathogenic alloantibody (126.8)

Abstract

Abstract Donor-reactive memory CD4 T cells are potent inducers of alloantibody (alloAb) even in the absence of the CD40/CD154 pathway. The goal of this study was to determine the cytokine requirements for CD40-independent help by memory CD4 T cells. Using donor-specific TCR transgenic T cells, we found that Th1 and Th17 memory CD4 T cells elicited high titers of alloAb in CD40-/- heart allograft recipients while Th2 cells failed to do so. The resulting anti-donor Abs differed in their specificity and the ability to mediate heart allograft pathology. Compared to Th1 cells, Th17 memory cells induced inferior Ab responses against donor MHC class I molecules. Anti-donor alloAb induced by Th1, but not by Th17 memory cells, caused diffuse C4d deposition in the graft capillaries. Blocking IFNγ in CD40-/- heart allograft recipients containing memory CD4 T cells drastically reduced serum IgG alloAb titers. In contrast, donor-reactive CD8 T cells were efficiently activated under these conditions indicating that the help for CD8 T cells is IFNγ-independent. Our data suggest that IFNγ secreted by donor-reactive memory CD4 T cells not only determines donor-reactive Ab isotypes, but also influences alloAb specificity and can thus affect allograft pathology.