FK506 markedly enhances apoptosis of antigen-stimulated peripheral T cells by down-regulation of Bcl-xL

Background. FK506 is a clinically effective immunosuppressive agent and promoter of immunologic tolerance. However, limited information is available about the mechanism of FK506-induced immunosuppression. Methods. In the present study, we investigated the molecular mechanism of FK506-mediated enhancement of apoptosis using in vivo activated T lymphocytes. We examined the effects of FM506 on apoptosis-related proteins in superantigen-stimulated peripheral T cells. Results. Injection of staphylococcal enterotoxin B (SEB) into BALB/c mice resulted in a selective apoptosis of splenic V beta 8-positive T cells after 48 hr, Injection of FK506 within 36 hr of SEE injection resulted in a marked enhancement of DNA fragmentation of splenic V beta 8(+) T cells, FK506 did not affect the expression of Fas antigen on SEE-activated V beta 8(+) T cells. As Bcl-2-related proteins are involved in apoptotic process, we also evaluated their role by examining the expression of Bcl-2, Bcl-x(L), and Bax on SEB-FR506-treated murine splenic T cells. Although SEE injection slightly increased the expressions of Bcl-2 and Bax on V beta 8(+) T cells, FK506 did not modulate Bcl-2 or Bax expression in these cells. In contrast, the expression of Ecl-x, on V beta 8(+) T cells, which was markedly induced by SEE, was abrogated by FK506, Conclusions. Our findings indicate FK506-induced enhancement of apoptosis of activated T cells is mediated by down-regulation of Bcl-x(L) expression on these cells. Our results also suggest that Bcl-x(L) is a critical determinant of apoptosis of activated T cell and may represent a potential target for new therapies designed to achieve immunological tolerance.