Signals delivered through TCR instruct IL-12 receptor (IL-12R) expression: IL-12 and tumor necrosis factor-α synergize for IL-12R expression at low antigen dose

Regulation of the IL-12 receptor (IL-12R) β2 chain has been suggested to function as a molecular switch in determining T cell phenotype. However, because most studies have been carried out under conditions in which cell proliferation was occurring, it has been difficult to distinguish between instructive and selective mechanisms in regulating this key receptor. Here, in the course of trying to understand the mechanism for synergy between IL-12 and TNF-α in up-regulating IFN-γ production, we find that when the stimulus through the TCR is too weak to induce cell proliferation, which would be needed for selection, IL-12 and TNF-α synergize to up-regulate not only IFN-γ, but also the IL-12Rβ2 chain, which triggers IFN-γ production. Neither cytokine alone was sufficient. This observation held true both in the absence of antigen-presenting cells (APC), when the stimulus was anti-CD3 on plastic, and in the presence of APC presenting ovalbumin peptide to TCR-transgenic T cells. In contrast, when the TCR signal was stronger, no cytokines were necessary to up-regulate the IL-12R. Our results support the strength of signal model in instructing Th phenotype, and suggest both an instructive role and, later, through the production of IFN-γ, a selective role, of this synergistic combination of cytokines in the preferential differentiation and expansion of Th1 cells.