REGULATION OF ALLOANTIGEN-MEDIATED T-CELL PROLIFERATION BY ENDOGENOUS INTERFERON-γ

Abstract

Background. Recent data suggest that interferon (IFN)-γ is not an essential mediator of acute rejection but, instead, is critical for the induction of long-term allograft acceptance. The in vivo mechanisms by which endogenous IFN-γ regulates the alloimmune response and thus facilitates the induction of long-term allograft survival are not known. Methods. We examined long-term cardiac and skin allograft survival, alloantigen-induced T-cell proliferation, and alloantigen-induced T-cell apoptosis in wild-type (IFN-γ^+/+) and IFN-γ gene-knockout (IFN-γ^−/−) mice treated with either B7-CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion. Results. We found that IFN-γ is essential for long-term allograft survival induced by treating mice with either B7-CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion. Alloantigen-induced T-cell proliferation in vivo was significantly greater in IFN-γ^−/− mice than in IFN-γ^+/+ mice, and T-cell costimulation blockade abrogated alloantigen-induced T-cell proliferation in wild-type mice but failed to do so in mice that lack IFN-γ. In contrast, alloantigen-induced T lymphocyte apoptosis in vivo did not differ between IFN-γ^+/+ and IFN-γ^−/− mice, and T-cell costimulation blockade enhanced alloantigen-induced T-cell apoptosis in both mouse strains. Conclusions. These data suggest that endogenous IFN-γ facilitates the induction of long-term allograft survival by limiting the proliferation of alloactivated T lymphocytes. The data also suggest that B7-CD28 T-cell costimulation blockade exerts immunosuppressive actions by inhibiting the proliferation of activated T lymphocytes and by promoting their apoptosis.