CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

BACKGROUND: Previous studies have shown that acute CD4 T-cell mediated cardiac allograft rejection requires donor major histocompatibility complex (MHC) Class II expression and can be independent of "indirect" antigen presentation. However, other studies suggested that indirect antigen presentation to CD4 T cells may play a primary role in cellular xenograft immunity. Thus, the relative roles of direct/indirect CD4 T cell reactivity against cardiac xenografts are unclear. In this study we set out to determine the role for indirect CD4 T cell reactivity in cardiac xenograft rejection. METHODS: Rat hearts were transplanted heterotopically into wild-type and immunodeficient mice. Recipients were untreated, treated with depleting antibodies, or reconstituted with wild-type cells. RESULTS: Antibody depletion confirmed that rat heart xenograft rejection in C57BI/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long term in B6 MHC Class II (C2D)-deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T cell deficiency alone, because transferred B6 CD4 T cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6ragl(-/-) recipients. Importantly, CD4 T cells did not reject rat hearts in C2Dragl(-/-) hosts, in contrast to results using cardiac allografts. "Direct" xenoreactive CD4 T cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro. CONCLUSIONS: Taken together, our results show that CD4 T cells are both necessary and sufficient for acute cardiac xenograft rejection and that host MFIC Class II is critical in this process. J Heart Lung Transplant 2012;31:1018-24 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.