Ahlers J D, Belyakov I M, Matsui S, Berzofsky J A
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Int Immunol. 2001 Nov;13(11):1433-42. doi: 10.1093/intimm/13.11.1433.
Regulation of the IL-12 receptor (IL-12R) beta2 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-alpha in up-regulating IFN-gamma 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-alpha synergize to up-regulate not only IFN-gamma, but also the IL-12Rbeta2 chain, which triggers IFN-gamma 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-gamma, a selective role, of this synergistic combination of cytokines in the preferential differentiation and expansion of Th1 cells.
白细胞介素12受体（IL-12R）β2链的调控被认为在决定T细胞表型方面起着分子开关的作用。然而，由于大多数研究是在细胞发生增殖的条件下进行的，因此很难区分调控这一关键受体的诱导机制和选择机制。在此，在试图理解IL-12和肿瘤坏死因子-α（TNF-α）在上调γ干扰素（IFN-γ）产生过程中的协同作用机制时，我们发现，当通过T细胞受体（TCR）的刺激过于微弱而无法诱导细胞增殖（这是选择所必需的）时，IL-12和TNF-α协同作用，不仅上调IFN-γ，还上调触发IFN-γ产生的IL-12Rβ2链。单独一种细胞因子都不足以产生这种效果。这一观察结果在没有抗原呈递细胞（APC）时（刺激为塑料上的抗CD3）以及在APC向TCR转基因T细胞呈递卵清蛋白肽时均成立。相反，当TCR信号更强时，上调IL-12R则不需要细胞因子。我们的结果支持信号强度模型在指导Th表型方面的作用，并表明这种细胞因子的协同组合在Th1细胞的优先分化和扩增中既具有诱导作用，随后又通过IFN-γ的产生具有选择作用。
