Cytotoxic pathways in the skin allograft rejection by CD4+ T cells

Background Two major mechanisms of T cell-mediated cytotoxicity are known: perforin-dependent and Fas-dependent cytotoxic pathways. Previous studies in vitro demonstrated that CD4(+) cytotoxic T lymphocytes use the Fas pathway as a primary cytotoxic mechanism, but the cytotoxic mechanisms used by CD4(+) T tells in vivo are unclear. Methods, We examined the cytotoxic pathways of CD4(+) T cells in vivo using a skin allograft model, in which athymic nu/nu mice were transplanted with skin allografts and reconstituted with purified CD4(+) T cells. Fas-deficient and perforin-deficient mice and anti-tumor necrosis factor (TNF)-alpha monoclonal antibody were used for inactivating each cytotoxic pathway in vivo. Results. The skin allografts from Fas-deficient mice were readily rejected by the athymic mice reconstituted with purified CD4(+) T cells. Perforin-deficient CD4(+) T cells could also reject Fas-deficient skin allografts. Furthermore, in vivo treatment with anti-TNF-alpha monoclonal antibody did not prevent the allograft rejection by CD4(+) T cells in the absence of both Fas and perforin pathways. Conclusions, These results indicate participation of undefined mechanisms other than Fas, perforin, and TNF-alpha pathways in CD4(+) T cell-mediated cytotoxicity in vivo.