STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection.
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.
Ludovic
L
Desvignes
Carl
C
Weidinger
Patrick
P
Shaw
Martin
M
Vaeth
Theo
T
Ribierre
Menghan
M
Liu
Tawania
T
Fergus
Lina
L
Kozhaya
Lauren
L
McVoy
Derya
D
Unutmaz
Joel D
JD
Ernst
Stefan
S
Feske
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D000071737:Stromal Interaction Molecule 1; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D015220:Calcium Channels; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1