Regulation of alloantigen-mediated T-cell proliferation by endogenous interferon-gamma - Implications for long-term allograft acceptance

Background. Recent data suggest that interferon (IFN)-gamma is not an essen tial mediator of acute rejection but, instead, is critical for the inductio n of long-term allograft acceptance. The in vivo mechanisms by which endoge nous IFN-gamma regulates the alloimmune response and thus facilitates the i nduction of long-term allograft survival are not known, Methods. We examined long-term cardiac and skin allograft survival, alloant igen-induced T-cell proliferation, and alloantigen-induced T-cell apoptosis in wild-type (IFN-gamma(+/+)) and IFN-gamma gene-knockout (IFN-gamma(-/-)) mice treated with either B7-CD28 T-cell costimulation blockade alone or B7 -CD28 T-cell costimulation blockade combined with donor splenocyte transfus ion. Results. We found that IFN-gamma is essential for longterm allograft surviv al induced by treating mice with either B7-CD28 T-cell costimulation blocka de alone or B7-CD28 T-cell costimulation blockade combined with donor splen ocyte transfusion. Alloantigen-induced T-cell proliferation in vivo was sig nificantly greater in IFN-gamma(-/-) mice than in IFN-gamma(+/+) mice, and T-cell costimulation blockade abrogated alloantigen-induced T-cell prolifer ation in wild-type mice but failed to do so in mice that lack. IFN-gamma. I n contrast, alloantigen-induced T lymphocyte apoptosis in vivo did not diff er between IFN-gamma(+/+) and IFN-gamma(-/-) mice, and T-cell costimulation blockade enhanced alloantigen-induced T-cell apoptosis in both mouse strai ns. Conclusions. These data suggest that endogenous IFN-gamma facilitates the i nduction of long-term allograft survival by limiting the proliferation of a lloactivated T lymphocytes, The data also suggest that B7-CD28 T-cell costi mulation blockade exerts immunosuppressive actions by inhibiting the prolif eration of activated T lymphocytes and by promoting their apoptosis.