Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Immunology Infectious disease Microbiology

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

  • Text
  • PDF
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

×

Figure 3

STIM1 controls AICD of T cells during chronic infection.

Options: View larger image (or click on image) Download as PowerPoint
STIM1 controls AICD of T cells during chronic infection.
(A) Infiltratio...
(A) Infiltration of T cells into the lungs of WT and Stim1CD4 mice at 114 d.p.i. with Mtb. T cells were stained with αCD3 antibody (red); images are representative of 5 mice per group. Original magnification, ×400. Arrows indicate inflammatory infiltrates with T cell accumulation. (B) Absolute numbers of CD4+ and CD8+ T cells in lungs of WT and Stim1CD4 mice determined by flow cytometry. Line graphs show mean ± SEM for 4 to 5 mice per group and time point. (C) Absolute numbers of in vitro–expanded splenic CD4+ and CD8+ T cells from uninfected WT and Stim1CD4 mice after a second stimulation with 2 μg/ml αCD3. Line graphs show mean ± SEM for 3 mice per group and time point. d.p.s., days post stimulation. (D and E) Apoptosis of in vitro–expanded CD4+ T cells isolated from spleens of uninfected WT and Stim1CD4 mice and restimulated with αCD3 for 6 and 24 hours; cells were analyzed by flow cytometry for annexin V and PI. Representative contour plots (D) and frequencies (E) of annexin V+ apoptotic CD4+ and CD8+ T cells 24 hours after restimulation with αCD3. Each dot represents 1 mouse from 2 independent experiments with 3 mice per group. (F) Apoptosis in primary T cells from the peripheral blood of a HD and a SOCE-deficient PAT with ORAI1 p.R91W mutation (10) after restimulation for 16 hours with αCD3/αCD28-coated beads. Histograms of annexin V staining are representative of 2 independent experiments. Statistical significance in B–E was calculated by Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts