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Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Although CD4 cells are major mediators in cellular rejection of
fetal pig pancreas (FPP) in the mouse, rejection still occurs in the
absence of CD4 cells, albeit with delayed kinetics. CD4
cell-independent mechanisms of cellular rejection are poorly
understood. To investigate the involvement of CD8 T cells in FPP
rejection and their activation requirements, we used mice transgenic
for anti-CD4 Ab; this is the most complete model of CD4 cell
deficiency. We showed that in such mice FPP was infiltrated with CD8
cells starting from 2 wk posttransplantation and FPP was eventually
rejected 8 wk posttransplantation. Ab depletion of CD8 cells greatly
improved the survival of FPP and reduced cell infiltration at the graft
site. This suggests that CD8 cells can mediate the rejection of porcine
xenografts in the absence of CD4 cells. This CD8-mediated rejection of
FPP is independent of their perforin-mediated lytic function, as graft
survival was not affected in mice deficient in perforin. The production
of IFN-
and IL-5 by the graft infiltrates indicates that CD8 cells
may act through cytokine-mediated mechanisms. Remarkably, in the
absence of CD4 cells, lymphocyte infiltration at the graft site was
absent in mice transgenic for CTLA4Ig such that the islet grafts
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.
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