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1 From the Kyoto Prefectural University and the 2 Osaka University School of Medicine, Japan; and 3 The Schepens Eye Research Institute, Boston, Massachusetts.
PURPOSE. To determine, with the use of mice genetically deficient in expression of CD4 or CD8 molecules, which T cells are responsible for rejection of orthotopic corneal allografts in mice.
METHODS. Corneas were prepared from major histocompatibility complex (MHC)–only incompatible, minor histocompatibility (H)–only incompatible, and MHC-plus-minor H incompatible donors and grafted orthotopically to eyes of CD4 knockout (KO), CD8KO, and wild-type control mice. Graft survival patterns were assessed clinically and compared. Mice that retained healthy corneal allografts beyond 8 weeks were evaluated for evidence of donor-specific tolerance and anterior-chamber–associated immune deviation (ACAID) using local adoptive transfer reactions and challenge with orthotopic skin allografts.
RESULTS. Corneas grafted to CD8KO mice were rejected with an incidence and tempo indistinguishable from that in wild-type control animals. By contrast, MHC-only, and minor-H–only incompatible corneal grafts survived indefinitely in eyes of CD4KO mice. Approximately 50% of corneal grafts that confronted CD4KO recipients with both MHC and minor H alloantigens experienced delayed rejection, whereas similar grafts in wild-type recipients were rejected acutely. CD4KO mice with long-accepted grafts displayed neither donor-specific ACAID nor allograft tolerance.
CONCLUSIONS. CD8+ T cells play little or no role in acute rejection of orthotopic corneal allografts. Instead, acute rejection is mediated almost exclusively by CD4+ T cells. Moreover, when corneal allografts survive for 8 weeks without acute rejection, CD4+ T cells promote donor-specific ACAID thereby insuring long-term graft acceptance.
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