Functional interaction between TGF-beta and IL-12 in human primary allogeneic cytotoxicity and proliferative response.
IL-12 is an important cytokine in the control of cell-mediated immunity. We have investigated the functional interaction of IL-12 with TGF-beta1, a cytokine involved in the regulation of growth and differentiation of immunocompetent cells, during human allogeneic response development. Using primary MLR, our data show that addition of exogenous TGF-beta at the sensitizing phase of the primary MLR resulted in the inhibition of both allogeneic cytotoxic and proliferative responses. The inhibitory effect of TGF-beta on allogeneic response involves an abrogation of IL-12/p70 production upon allostimulation. In contrast to its effect on IL-12 production, TGF-beta did not alter the expression of IL-12R beta1-chain (IL-12R beta) in T cells induced upon allogeneic activation. Addition of exogenous IL-12 or IFN-gamma in the MLR cultures in the presence of TGF-beta did not result in reversal of CTL generation and T cell proliferation. Interestingly, TGF-beta was efficient in down-regulating IL-12 responsiveness of alloactivated T cells as well as TCR-alphabeta or TCR-gammadelta alloreactive T cell clones. These studies suggest that the inhibitory effect of TGF-beta on the development of human allogeneic proliferation and cytotoxic responses involves an additional mechanism associated with an interference with IL-12 pathway.
Pardoux
C
C
Laboratory of Cytokines and Antitumor Immunity, CJF 94-11 INSERM, Gustave Roussy Institute, Villejuif, France.
Asselin-Paturel
C
C
Chehimi
J
J
Gay
F
F
Mami-Chouaib
F
F
Chouaib
S
S
D000328:Adult; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D018664:Interleukin-12 / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D007519:Isoantigens; D018123:Receptors, Interleukin; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma