Rapid rejection of HLA-A2 transgenic skin graft due to indirect allorecognition

At present, it is not clear whether xenogeneic MHC molecules are recognized by T cells directly or indirectly through self-MHC-restricted presentation in a transplantation setting. We have transplanted skin from HLA-A2 transgenic (B6.A2) to nontransgenic C57BL/6 (B6) mice and investigated the subsequent mouse T-cell responses to HLA molecules, in vivo and in vitro. Skin transplanted from transgenic B6.A2 to B6 mice was rejected rapidly, in 12-16 days. Although naive B6 mice did not respond to B6.A2 splenocytes in vitro, spleen cells from mice that underwent transplantation showed strong proliferative responses. An anti-B6.A2 T-cell line from mice that underwent transplantation made proliferative responses to B6.A2 splenocytes but did not recognize HLA-A2 on human cells or transfected allogeneic mouse cells. The indirect, self-H-2-restricted recognition of HLA-A2 implied by this was confirmed by the finding that lysates of HLA-A2-positive, but not HLA-A2-negative, human B cells were stimulatory when pulsed onto syngeneic antigen-presenting cells and by inhibition of anti-B6.A2 proliferation with both anti-mouse MHC class I and class II antibodies. Our results suggest that indirect recognition of xenogeneic MHC antigen plays a predominant role in graft rejection.