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STIM1 controls T cell–mediated immune regulation and inflammation in chronic infection
Ludovic Desvignes, … , Joel D. Ernst, Stefan Feske
Ludovic Desvignes, … , Joel D. Ernst, Stefan Feske
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2347-2362. https://doi.org/10.1172/JCI80273.
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Research Article Immunology Infectious disease Microbiology

STIM1 controls T cell–mediated immune regulation and inflammation in chronic infection

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Abstract

Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell–mediated immune regulation during chronic Mtb infection. Compared with WT animals, mice with T cell–specific Stim1 deletion died prematurely during the chronic phase of infection and had increased bacterial burdens and severe pulmonary inflammation, with increased myeloid and lymphoid cell infiltration. Although STIM1-deficient T cells exhibited markedly reduced IFN-γ production during the early phase of Mtb infection, bacterial growth was not immediately exacerbated. During the chronic phase, however, STIM1-deficient T cells displayed enhanced IFN-γ production in response to elevated levels of IL-12 and IL-18. The lack of STIM1 in T cells was associated with impaired activation-induced cell death upon repeated TCR engagement and pulmonary lymphocytosis and hyperinflammation in Mtb-infected mice. Chronically Mtb-infected, STIM1-deficient mice had reduced levels of inducible regulatory T cells (iTregs) due to a T cell–intrinsic requirement for STIM1 in iTreg differentiation and excessive production of IFN-γ and IL-12, which suppress iTreg differentiation and maintenance. Thus, STIM1 controls multiple aspects of T cell–mediated immune regulation to limit injurious inflammation during chronic infection.

Authors

Ludovic Desvignes, Carl Weidinger, Patrick Shaw, Martin Vaeth, Theo Ribierre, Menghan Liu, Tawania Fergus, Lina Kozhaya, Lauren McVoy, Derya Unutmaz, Joel D. Ernst, Stefan Feske

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Figure 7

STIM1 regulates the development, but not the stability, of iTregs.

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STIM1 regulates the development, but not the stability, of iTregs.
(A) F...
(A) Frequencies of CD25+FOXP3+ iTregs after in vitro αCD3/αCD28 stimulation of naive splenic CD4+ T cells from WT or Stim1CD4 mice with or without TGF-β (untreated) for 3 days. (B) iTreg differentiation of human CD4+ T cells from a HD or PAT with ORAI1 p.R91W mutation (PAT) (10) after αCD3/αCD28 stimulation with or without TGF-β for 5 days in vitro. Flow cytometry dot plots showing Helios and FOXP3 expression are representative of 3 independent experiments. (C and D) Microarray analysis of WT versus Stim1CD4 iTregs. (C) Venn diagram (left) showing more than 100 iTreg signature genes (see Methods) differentially regulated in Stim1CD4 T cells. Scatter plot (right) of robust multi-array average (RMA) expression of genes that are part (orange) or not part (blue) of the iTreg signature. (D) Bar graphs representing fold changes of iTreg genes in Stim1CD4 cells (P < 0.05 for genes shown). (E) Frequencies of splenic Tregs 16 days after adoptive transfer of naive CD4+ T cells from WT or Stim1CD4 mice. Each symbol represents 1 mouse; data are from 2 independent experiments. (F–H) Unimpaired iTreg maintenance after inducible deletion of Stim1 in vivo. (F) Experimental design (see Methods). (G) SOCE in adoptively transferred CD4+ T cells from mesenteric lymph nodes of mice injected (+Tam) or not (–Tam) with tamoxifen. Mean Fluo-4 fluorescence (F) over baseline (F0) (± SEM) measured by flow cytometry; data are representative of 3-4 mice per group. (H) Frequencies of FOXP3+ iTregs (left) and IL-2+CD4+ T cells (after PMA/ionomycin stimulation for 6 hours; right) isolated from mesenteric lymph nodes of recipient mice. Statistical significance calculated by Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.

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