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 RT1A^a class I MHC‐disparate rat cardiac and skin allografts by high‐responder PVG RT1^u 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‐RT1^u 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‐RT1^u 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.