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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 1

STIM1 in T cells is required to control chronic Mtb infection in mice.

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STIM1 in T cells is required to control chronic Mtb infection in mice.
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(A and B) Survival curves (A) and lung bacterial burden (B) of Stim1CD4 and WT control mice infected with 100 CFU of aerosolized Mtb strain H37Rv. Results are representative of 3 independent experiments. (C) H&E stains of lung sections at 114 d.p.i. Pictures are representative of 5 mice per group. Original magnification, ×40. (D) Averaged total numbers of live cells isolated from the lungs of 3 to 5 mice per group and time point. (E) Open alveolar spaces quantified from histological sections in part C of 4–5 mice per group and time point using ImageJ software. Statistical significance was calculated by Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.
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