IMMUNOSUPPRESSIVE EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA - INHIBITION OF THE INDUCTION OF IA-ANTIGEN ON LANGERHANS CELLS BY CYTOKINES AND OF THE CONTACT HYPERSENSITIVITY RESPONSE

Recent reports show that transforming growth factor (TGF)-beta exerts a variety of immunosuppressive activities. The present study focuses on the effects of TGF-beta-1 on expression of Ia antigen by Langerhans cells. Although TGF-beta-1, in concentrations from 0.001 to 100-mu-g/ml, has no effect on constitutive expression of Ia antigen on these cells, the in vitro up-regulation of Ia antigen on the surface of LC by interleukin (IL)-1, tumor necrosis factor-alpha, interferon-gamma, IL-3, and granulocyte/macrophage-colony stimulating factor is inhibited by the concommitant addition of 1-mu-g/ml TGF-beta-1. In contrast, TGF-beta-1 has no effect on the up-regulation induced by IL-2 or IL-6. In this report, the activity of TGF-beta closely resembles that of Cyclosporine A (CsA). Similar results are seen in vivo when either TGF-beta-1 (5-mu-g, intraperitoneally [ip], daily on days 0-3) or CsA (1 mg, subcutaneously [sc], twice daily on days 0-3) are given together with IL-2 (500 U, intraperitoneally [ip], twice daily on days 1-3) or interferon-gamma (4,000 U, ip, twice daily on days 1-3). Given the important role of Ia expression in cell-mediated immune reactions, the effect of TGF-beta on contact sensitivity was next investigated. In doses of 5-mu-g, ip, daily on days 6-8, TGF-beta inhibits the expression of contact reactivity in animals sensitized on day 0 and challenged on day 7. In contrast, no effect is observed on the induction of contact sensitivity in mice given TGF-beta-1 on days - 1 to 2, sensitized on day 0, and challenged on day 7. The possible importance of antagonism between TGF-beta and other cytokines, especially IFN-gamma, involved in the elicitation of contact hypersensitivity reactions is discussed.