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

Background. Fas ligand (FasL)-Fas and tumor necrosis factor alpha (TNF alpha)-tumor necrosis factor receptor (TNFR) interactions regulate immune responses and contribute to self-tolerance by mediating antigen-driven T cell apoptosis. It is not known whether Fast and TNF alpha, expressed by the recipient's lymphoid or nonlymphoid cells, are essential for the apoptosis of alloreactive 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 addition, we studied cardiac allograft survival in gld mice injected with TNF alpha-neutralizing antibody. Allograft acceptance (graft survival >100 days) was induced by treating the recipients with CTLA4Ig, a recombinant fusion protein that blocks B7-CD28 T cell costimulation, In vivo alloantigen-driven apoptosis of mature CD4(+) and CD8(+) T lymphocytes was analyzed in mice 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 acceptance in gld recipients injected with TNE alpha-neutralizing antibody. In 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 alpha 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 are not obligatory for the induction of long-term allograft acceptance by CTLA4Ig and (2) FasL- and TNF alpha-independent death pathways contribute to alloantigen-driven T cell apoptosis.