Institut Cochin, Paris Descartes Université, CNRS UMR8104, INSERM U1016, Paris, France.
Paris Diderot Université, Paris, France.
Elife. 2017 Dec 14;6:e27215. doi: 10.7554/eLife.27215.
Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on calcineurin activation. Accordingly, in vivo calcineurin inhibition leads the most self-reactive naive CD4 T cells to adopt the phenotype of their less self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state.
持续接触自身主要组织相容性复合体配体对于幼稚 CD4 T 细胞的存活至关重要。我们之前已经表明，由此产生的紧张型 TCR 信号也会影响它们在被激活后的命运，增加它们分化为诱导/外周调节性 T 细胞的能力。为了解析控制这一过程的分子机制，我们在此集中研究 TCR 信号级联，并证明细胞内钙离子水平的升高足以调节小鼠幼稚 CD4 T 细胞的表型，并增加它们对调节性 T 细胞极化信号的敏感性，这两个过程都依赖于钙调神经磷酸酶的激活。因此，体内钙调神经磷酸酶抑制会导致最具自身反应性的幼稚 CD4 T 细胞表现出与其反应性较低的细胞对应物相似的表型。总之，我们的研究结果表明，钙介导的钙调神经磷酸酶途径的激活作为一个变阻器，在稳态下调节幼稚 CD4 T 细胞的表型和效应潜力。
