The proinflammatory effects of CD95L

have raised questions about its contribution to immune privilege (3, 5, 16 ), tolerance, and graft survival (8–10). Although it triggers apoptosis in T lymphocytes (2) (Fig. 2D), CD95L unexpectedly stimulated PMN activation. As described for other PMN stimulants (17), this activity is dependent on its ability to enhance p38 MAPK activity (Fig. 3). PMNs directly mediate cytolysis of CD95L cells, and this effect is inhibited by TGF-b, which is present in the aqueous humor (13). TGF-b also plays a role in immune tolerance through this mechanism and its effect on T cell proliferation. Although it inhibits p38 MAPK activity in other cells (18), its effect on innate immune responses mediated by neutrophils was previously unknown. Together CD95L and TGF-b promote lymphocyte clonal deletion and suppress inflammation. Thus, providing a microenvironment that includes both of these elements may aid in amelioration of allograft rejection at nonprivileged sites. Both CD95L and TGF-b1 have also been detected in tumors, particularly in the extracellular matrix, where they may inhibit immunologic recognition of malignancies (6, 19). Successful immune therapies for cancer are likely to require strategies to reverse this mechanism of immune suppression in vivo.