Alloantigen-driven T cell death mediated by Fas ligand and tumor necrosis factor-alpha is not essential for the induction of allograft acceptance

Background. Fas ligand (FasL)-Fas and tumor necrosis factor alpha (TNF alph a)-tumor necrosis factor receptor (TNFR) interactions regulate immune respo nses and contribute to self-tolerance by mediating antigen-driven T cell ap optosis. It is not known whether Fast and TNF alpha, expressed by the recip ient's lymphoid or nonlymphoid cells, are essential for the apoptosis of al loreactive T lymphocytes and the induction of allograft acceptance. Methods. We compared the survival of fully allogeneic vascularized cardiac allografts between wildtype (wt) and Fast-mutant (gld) recipient mice, In a ddition, we studied cardiac allograft survival in gld mice injected with TN F alpha-neutralizing antibody. Allograft acceptance (graft survival >100 da ys) was induced by treating the recipients with CTLA4Ig, a recombinant fusi on protein that blocks B7-CD28 T cell costimulation, In vivo alloantigen-dr iven apoptosis of mature CD4(+) and CD8(+) T lymphocytes was analyzed in mi ce repeatedly stimulated with allogeneic splenocytes. Results. We found that CTLA4Ig induces 100% longterm acceptance of cardiac allografts in wt and gld mice. Similarly, CTLA4Ig induced 100% allograft ac ceptance in gld recipients injected with TNE alpha-neutralizing antibody. I n vivo alloantigen-driven apoptosis of mature CD4(+) and CD8(+) T cells was significantly reduced in gld mice and in wt mice treated with anti-TNF alp ha antibody. However, neutralizing TNF alpha activity in gld mice failed to abrogate alloantigen-driven T cell apoptosis. Conclusions. These data indicate that: (1) Fast and TNF alpha expression ar e not obligatory for the induction of long-term allograft acceptance by CTL A4Ig and (2) FasL- and TNF alpha-independent death pathways contribute to a lloantigen-driven T cell apoptosis.