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Cellular and Molecular Immunology Laboratory, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114
Corneal transplantation represents an interesting model to
investigate the contribution of direct vs indirect Ag recognition
pathways to the alloresponse. Corneal allografts are naturally devoid
of MHC class II+ APCs. In addition, minor Ag-mismatched
corneal grafts are more readily rejected than their 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
have determined the Ag specificity, frequency, and phenotype of T cells
activated through direct and indirect pathways in BALB/c mice
transplanted orthotopically with fully allogeneic C57BL/6 corneas. In
this combination, only 60% 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-
-producing CD8+ T cells
recognizing donor MHC in a direct fashion. Surprisingly,
CD8+ T cells activated directly were not required for graft
rejection. In nonrejecting mice, no T cell responses were detected.
Strikingly, peripheral sensitization to allogeneic MHC molecules in
these mice induced acute rejection of corneal grafts. We conclude that
only CD4+ T cells activated via indirect allorecognition
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 receive an additional signal provided by
professional APCs in the periphery.
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