Background Two major mechanisms of T cell-mediated cytotoxicity are known:
perforin-dependent and Fas-dependent cytotoxic pathways. Previous studies i
n vitro demonstrated that CD4(+) cytotoxic T lymphocytes use the Fas pathwa
y as a primary cytotoxic mechanism, but the cytotoxic mechanisms used by CD
4(+) 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-defici
ent and perforin-deficient mice and anti-tumor necrosis factor (TNF)-alpha
monoclonal antibody were used for inactivating each cytotoxic pathway in vi
vo.
Results. The skin allografts from Fas-deficient mice were readily rejected
by the athymic mice reconstituted with purified CD4(+) T cells. Perforin-de
ficient CD4(+) T cells could also reject Fas-deficient skin allografts. Fur
thermore, in vivo treatment with anti-TNF-alpha monoclonal antibody did not
prevent the allograft rejection by CD4(+) T cells in the absence of both F
as and perforin pathways.
Conclusions, These results indicate participation of undefined mechanisms o
ther than Fas, perforin, and TNF-alpha pathways in CD4(+) T cell-mediated c
ytotoxicity in vivo.