Role of CD4(+) and CD8(+) T cells in allorecognition: Lessons from cornealtransplantation

Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the allorespo nse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addi tion, minor Ag-mismatched corneal grafts are more readily rejected than the ir MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we hav e determined the Ag specificity, frequency, and phenotype of T cells activa ted through direct and indirect pathways in BALB/c mice transplanted orthot opically with fully allogeneic C57BL/6 corneas. In this combination, only 6 0% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4(+) T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-gamma -producing CD8(+) T cel ls recognizing donor MHC in a direct fashion. Surprisingly, CD8(+) T cells activated directly were not required for graft rejection. In nonrejecting m ice, no T cell responses were detected. Strikingly, peripheral sensitizatio n to allogeneic MHC molecules in these mice induced acute rejection of corn eal grafts. We conclude that only CD4(+) T cells activated via indirect all orecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8(+) T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they rec eive an additional signal provided by professional APCs in the periphery.