TRAIL‐TRAIL Receptor interactions between donor T cells and host B cells are required for induction of autoimmunity in chronic graft‐versus‐host disease

Abstract

TNF‐related apoptosis‐inducing ligand (TRAIL) mediates the apoptosis of transformed and immune cells and also exerts immunoregulatory functions. Our studies in the parent‐into‐F1 model of chronic graft‐vs‐host disease (cGVHD) demonstrated that TRAIL expression on T cells exacerbates lupus by positively regulating CD4+ T helper cell numbers and sustaining T cell help for B cells. To determine whether direct interactions between TRAIL on donor T cells and TRAIL‐R on autoreactive host B cells are required for induction of autoimmunity we used TRAIL‐R KO as recipients in the bm12‐>B6 model of cGVHD. When cGVHD was induced by injecting Bm12 donor cells into TRAIL R1/DR5‐KO B6 mice, parameters of cGVHD were attenuated compared to cGVHD induced in WT B6 mice. Specifically, the expression of activation markers on host B cells were significantly lower in TRAIL R1/DR5‐KO B6 compared to WT B6 hosts (80±20 vs 362±51 for MHC class II MCF, 19± 6.7 vs 54.1±9.2 for Fas and 38.9±8 vs 65.3±6.4 for B7‐2; p=0.001 for all three comparisons). In addition anti ss‐DNA autoantibody levels were significantly lower in TRAIL R1/DR5‐KO B6 hosts compared to WT B6 hosts. In conclusion, these results suggest that the direct interactions between TRAIL on donor CD4+ T cells and TRAIL‐R on host B cells may be essential for the activation of autoreactive B cells and their differentiation into autoantibody producing cells.