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

被引：0

作者：

Zhong, Li ^{[1
]}

Wang, Yin-Hu ^{[1
]}

Kahlfuss, Sascha ^{[1
,6
]}

Jishage, Miki ^{[1
]}

Mcdermott, Maxwell ^{[1
]}

Yang, Jun ^{[1
]}

Tao, Anthony Y. ^{[1
]}

Hu, Ke ^{[1
]}

Noyer, Lucile ^{[1
]}

Raphael, Dimitrius ^{[1
]}

Patel, Devisha ^{[1
]}

Knight, Tristan E. ^{[2
,7
]}

Chitlur, Meera ^{[2
,3
]}

Machaca, Khaled ^{[4
,5
]}

Feske, Stefan ^{[1
]}

机构：

[1] NYU, Grossman Sch Med, Dept Pathol, New York, NY 10016 USA

[2] Childrens Hosp Michigan, Div Pediat Hematol Oncol, Detroit, MI USA

[3] Cent Michigan Univ, Coll Med, Detroit, MI USA

[4] Weill Cornell Med, Calcium Signaling Grp, Res Dept, Doha, Qatar

[5] Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA

[6] Otto von Guericke Univ, Med Fac, Inst Mol & Clin Immunol, Inst Med Microbiol & Hosp Hyg, Magdeburg, Germany

[7] Kapiolani Med Ctr Women & Children, Burns Sch Med, Honolulu, HI USA

来源：

NATURE IMMUNOLOGY | 2025年 / 26卷 / 03期

基金：

美国国家卫生研究院;

关键词：

OPERATED CA2+ ENTRY; TRANSCRIPTION FACTOR; IMMUNE-RESPONSES; INTERFERON-GAMMA; GENE-REGULATION; T-HELPER-1; TH1; CELLS; ACTIVATION; EFFECTOR; INDUCTION;

D O I：

10.1038/s41590-025-02089-8

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

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 beta 1 and beta 2 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.

引用

页码：484 / 496

页数：33

共 64 条

[1] Szabo S.J., Et al., A novel transcription factor, T-bet, directs Th1 lineage commitment, Cell, 100, pp. 655-669, (2000)
[2] Lazarevic V., Glimcher L.H., T-bet in disease, Nat. Immunol, 12, pp. 597-606, (2011)
[3] Yang R., Et al., Human T-bet governs innate and innate-like adaptive IFN-gamma immunity against mycobacteria, Cell, 183, pp. e1831-e1847, (2020)
[4] Pritchard G.H., Kedl R.M., Hunter C.A., The evolving role of T-bet in resistance to infection, Nat. Rev. Immunol, 19, pp. 398-410, (2019)
[5] Lighvani A.A., Et al., T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells, Proc. Natl Acad. Sci. USA, 98, pp. 15137-15142, (2001)
[6] Afkarian M., Et al., T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4(+) T cells, Nat. Immunol, 3, pp. 549-557, (2002)
[7] Schulz E.G., Mariani L., Radbruch A., Hofer T., Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12, Immunity, 30, pp. 673-683, (2009)
[8] Szabo S.J., Dighe A.S., Gubler U., Murphy K.M., Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells, J. Exp. Med, 185, pp. 817-824, (1997)
[9] Sekiya T., Yoshimura A., In vitro Th differentiation protocol, Methods Mol. Biol, 1344, pp. 183-191, (2016)
[10] van de Berg P.J., Et al., Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature, J. Infect. Dis, 202, pp. 690-699, (2010)

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