TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES ANTIGEN-SPECIFIC UNRESPONSIVENESS IN NAIVE T-CELLS

Transforming growth factor-beta 1 (TGF-beta 1) is a cytokine with comp lex immunomodulatory effects including the ability to inhibit the onse t or severity of autoimmune disease. This study was designed to test t he possibility that one mechanism by which TGF-beta 1 exerts its immun osuppressive effects is by inducing antigen (Ag)-specific unresponsive ness in CD4(+) cells. TGF-beta 1 was shown here to inhibit the Ag-spec ific proliferation of naive CD4(+) cells from T cell receptor (TCR) tr ansgenic mice. More importantly, the naive CD4(+) cells exposed to TGF -beta 1 and Ag, but not to TGF-beta 1 alone, in primary cultures were unable to proliferate or secrete IL-2 in response to a subsequent Ag c hallenge following removal of TGF-beta 1 from the cultures. Anti-CD2s mAb partially blocked the Ag-specific inactivation induced by TGF-beta 1 in naive CD4(+) cells. The inhibitory effects of TGF-beta 1 on CD4( +) cells are not mediated by alterations in APC costimulation since TG F-beta 1 did not inhibit the Ag-induced expression of MHC class II mol ecules, CD80 or CD86 on splenic APC. Taken together, the results sugge st that the immunosuppressive activities of TGF-beta 1 encompass direc t induction of Ag-specific unresponsiveness in naive CD4(+) cells.