ADOPTIVELY TRANSFERRED CD4(-() LYMPHOCYTES FROM CD8)-MICE ARE SUFFICIENT TO MEDIATE THE REJECTION OF MHC CLASS-II OR CLASS-I DISPARATE SKIN-GRAFTS/

Recent studies revealed that CD4(+) cells initiate allograft rejection through direct recognition of allogeneic MHC class It Ags and indirec t recognition of MHC peptides processed by self APCs. Both pathways we re shown to help CD8(+) cells that eventually lysed allogeneic MHC cla ss I-presenting targets, There was little evidence, however, that CD4( +) cells are sufficient for graft rejection, We studied skin graft rej ection by CD8-deficient (CD8 -/-) mice, We showed that BALB/cj (H-2(d) ) CD8 -/- mice could reject allogeneic skin from C57BL/6j (H-2(b)) mic e deficient in MHC class I or in MHC class II Ags, To understand the r ole of CD4(+) cells in this process, we isolated them from CD8 -/- mic e and transferred them to BALB/cj nude mice that had been grafted with allogeneic skin (H-2(b)) from animals deficient in MHC class I or in MHC class II, Nude mice injected with CD4(+) cells rejected MHC class II and, albeit more slowly, MHC class I disparate skins, We showed in vitro evidence that CD4(+) cells were not cytotoxic toward MHC class I or MHC class If disparate targets and that they recognized MHC class I allogeneic targets through indirect recognition, CD4(+) cells produc ed Th1 cytokines, but not IL-4, following stimulation with allogeneic cells, Furthermore, intragraft TNF-alpha was elevated in skin grafted onto nude mice reconstituted with CD4(+) cells compared with the nonre constituted mice, This suggests that MHC class II- or MHC class I-guid ed CD4(+) cells alone are sufficient to induce rejection by the genera tion of cytokine-induced lesions.