T-CELL RECOGNITION OF XENO-MHC PEPTIDES DURING CONCORDANT XENOGRAFT REJECTION

T cell recognition of xenoantigens is likely to play a key role in rej ection of xenografts surviving hyperacute and delayed xenograft reject ion, but the mechanisms of how this might occur are unknown, We used s ynthetic rat class II MHC peptides to study the role of the indirect p athway, where processed xenogeneic MHC antigens are presented in the c ontext of self MHC, in a concordant xenograft rejection model in vivo, Mice of four different strains, BALB/c, B10.A, CBA/ca, and C57BL/6j, were immunized with a mixture of rat class II MHC 25-mer xenopeptides representing the full-length sequence of the beta chain hypervariable domain of either RT1.D-u (DR and I-E like) or RT1.B-u (DQ and I-A like ) of the Wistar-Furth (WF) (RT1(u)) rat, Draining lymph node cells wer e capable of recognizing and proliferating to specific class II xeno-M HC peptides, The immunogenicity of the different peptides varied with the responder mouse strain, Responder T cells were CD4(+), and were in hibited by anti-I-A and anti-I-E antibodies, We then examined the prol iferative response of T cells from B10.A primed by WF skin or vascular ized cardiac xenografts to the class II MHC xenopeptides, when present ed by naive B10.A splenic antigen-presenting cells, These T cells were capable of proliferating to the same xeno-MHC peptides shown to be im munogenic by immunization, These data confirm the occurrence of self-r estricted T cell recognition of xeno-MHC peptides in xenograft rejecti on, and provide the rationale for further investigating the role of th e indirect pathway of recognition in xenotransplantation.