CD4+ T cell‐mediated rejection of major histocompatibility complex class I‐disparate grafts: A role for alloantibody

Experimental studies of the T cell requirement for rejection of class I major histocompatibility complex (MHC)‐disparate grafts have generated controversy over both the autonomy of CD8+ T cells and the mechanism whereby CD4+ T cells are able to independently mediate rejection. In this study of rejection of RT1Aa class I MHC‐disparate rat cardiac and skin allografts by high‐responder PVG RT1u recipients, we show that elimination of CD8+ T cells [by anti‐CD8 monoclonal antibody (mAb) administration in vivo] fails to prolong graft survival, whereas partial depletion of CD4+ T cells (by anti‐CD4 mAb treatment) markedly delays rejection of class I‐disparate heart grafts, and marginally prolongs survival of skin grafts. Anti‐CD4‐treated PVG‐RT1u athymic nude rats reconstituted with CD8+ T cells failed to reject class I‐disparate skin grafts for several weeks and eventual rejection correlated with re‐emergence of a small number of donor derived CD4+ T cells. Conversely, anti‐CD8‐treated nude rats reconstituted with CD4+ T cells alone rapidly rejected class I‐disparate skin grafts. Passive transfer of anti‐class I immune serum to anti‐CD4‐treated euthymic recipients promptly restored their ability to specifically reject a class I‐disparate heart graft. Similarly, passive transfer of immune serum to PVG‐RT1u nude rats bearing skin allografts caused destruction of class I‐disparate but not third‐party grafts. These results demonstrate that CD4+ T cells are both necessary and sufficient to cause rejection of class I‐disparate heart and skin grafts in this model and that CD4+ T cell‐dependent alloantibody plays a decisive role in effecting rejection.