Without CD4 help, CD8 rejection of pig xenografts requires CD28 costimulation but not perforin killing

Although CD4 cells are major mediators in cellular rejection of fetal pig p ancreas (FPP) in the mouse, rejection still occurs in the absence of CD4 ce lls, albeit with delayed kinetics. CD4 cell-independent mechanisms of cellu lar rejection are poorly understood. To investigate the involvement of CD8 T cells in FPP rejection and their activation requirements, we used mice tr ansgenic for anti-CD4 Ab; this is the most complete model of CD4 cell defic iency. We showed that in such mice FPP was infiltrated with CD8 cells start ing from 2 wk posttransplantation and FPP was eventually rejected 8 wk post transplantation. Ab depletion of CD8 cells greatly improved the survival of FPP and reduced cell infiltration at the graft site. This suggests that CD 8 cells can mediate the rejection of porcine xenografts in the absence of C D4 cells. This CDS-mediated rejection of FPP is independent of their perfor in-mediated lytic function, as graft survival was not affected in mice defi cient in perforin. The production of IFN-gamma and IL-5 by the graft infilt rates indicates that CD8 cells may act through cytokine-mediated mechanisms . Remarkably, in the absence of CD4 cells, lymphocyte infiltration at the g raft site was absent in mice transgenic for CTLA4Ig such that the islet gra fts flourished beyond 24 wk. In contrast, rejection was little affected by CD40 ligand deficiency. Therefore, we show that CD8 cells are activated to mediate FPP rejection independent of perforin and that this CD4-independent activation of CD8 cells critically depends on B7/CD28 costimulation.