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<p>Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca<sup>2+</sup> entry (SOCE) and T cell activation. T helper 1 (T<sub>H</sub>1) cells, which express T-bet (encoded by <i>TBX21</i>), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T<sub>H</sub> lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in <i>STIM1</i>, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the <i>TBX21</i> enhancer and enables NFAT to synergize with STAT1 to mediate <i>TBX21</i> expression. While SOCE-deficient CD4<sup>+</sup> T cells have reduced expression of <i>TBX21</i> in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.</p>

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STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation

  • 期刊论文

  • 发表日期：

    2025年2月21日

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  • Li Zhong,
  • Yin-Hu Wang,
  • Sascha Kahlfuss,
  • Miki Jishage,
  • Maxwell McDermott,
  • Jun Yang,
  • Anthony Y. Tao,
  • Ke Hu,
  • Lucile Noyer,
  • Dimitrius Raphael,
  • Devisha Patel,
  • Tristan E. Knight,
  • Meera Chitlur,
  • Khaled Machaca,
  • Stefan Feske

摘要

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca2+ entry (SOCE) and T cell activation. T helper 1 (TH1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other TH lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4+ T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.