Detection of minor alloantigen-specific cytotoxic T cells after rejection of murine orthotopic corneal allografts - Evidence that graft antigens are recognized exclusively via the "indirect pathway"

Background. The immune mechanisms by which corneal allografts are rejected in normal ocular graft beds have not been identified. Both accepters and re jectors of these types of grafts display donor-specific delayed hypersensit ivity and in vitro proliferating primed T cells, yet neither develop conven tional, donor-specific cytotoxic T cells. We wished to determine whether un conventional donor-specific cytotoxic T cells are generated in rejector mic e that recognize donor minor alloantigens presented by recipient major hist ocompatibility complex (MHC) molecules. Methods. BALB/c mice received orthotopic corneal allografts from C57BL/10 d onors in normal eyes. At 4 weeks (when 50% of grafts can be designated as r ejected), primed cytotoxic T lymphocyte (CTL) activity in draining lymph no des and spleen was assayed on targets selected to present donor-type minor H antigens on recipient MHC molecules. Control mice received heterotopic co rneal allografts and were similarly examine. Results. Lymphoid organs of recipients that rejected orthotopic or heteroto pic corneal allografts contained CTL that lysed targets expressing donor-ty pe minor H antigens presented by recipient MHC molecules. By contrast, no C TL activity was detected from lymphoid cells of recipients that accepted or thotopic corneal allografts, Rejection of orthotopic corneal allografts pla ced into normal mouse eyes correlates directly with the generation of donor -specific CTL that recognize minor H antigens in the context of recipients MHC molecules. Conclusions. These results indicate the indirect pathway of alloantigen pre sentation is the only pathway operative in the process by which orthotopic corneal allografts are rejected. The roles of emigrant Langerhans cells and corneal lymphatics in the indirect pathway are discussed.