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

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

doi:10.1172/jci80273

Cited by 56 publications

(61 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in contrast to the important role of SOCE in T cells and their ability to provide immunity to infection (9, 10) and to mediate inflammation in the context of autoimmunity (47, 76, 87). Genetic or pharmacological inhibition of SOCE in lymphocytes prevents T cell mediated autoimmunity and inflammation in preclinical models of diseases such as multiple sclerosis (76, 87), inflammatory bowel disease (47), skin allograft rejection (47) and allergic asthma (88), which may be utilized for the treatment of diseases in human patients.…”

Section: Discussionmentioning

confidence: 81%

“…Patients lacking SOCE due to mutations in ORAI1 or STIM1 genes are severely immunodeficient and suffer from recurrent, often life-threatening infections with viral, bacterial, mycobacterial and fungal pathogens (6). While many infections can be attributed to impaired T cell-mediated adaptive immunity (6, 9, 10, 72), the patients’ frequent bacterial and mycobacterial (BCG) infections could be compounded by defective SOCE in innate immune cells resulting in an impaired function of neutrophils, macrophages and DCs. Consistent with the essential role of STIM1 and STIM2 in SOCE in T cells (41) and B cells (73), we found that conditional deletion of Stim1 and Stim2 genes in hematopoietic cells of mice completely abolishes SOCE in macrophages and DCs.…”

Section: Discussionmentioning

confidence: 99%

“…These patients have recurrent and chronic infections with viruses, bacteria and fungal pathogens that have been attributed to impaired T cell function because of severely impaired proliferation and cytokine production of patient T cells in vitro. T cell-specific deletion of Stim1 gene expression in mice impairs immunity to Mycobacterium tuberculosis (9) and deletion of both Stim1 and Stim2 compromises antiviral immunity due to impaired CD4 + and CD8 + T cell responses (10). In contrast to the well documented function of CRAC channels in T cells, their role in innate immune responses is not well defined and it is unclear if defects in myeloid cells contribute to the immunodeficiency of ORAI1 and STIM1 deficient patients.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells

Vaeth

Zee

Concepcion

et al. 2015

The Journal of Immunology

Self Cite

102

View full text Add to dashboard Cite

Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels is essential for immunity to infection. CRAC channels are formed by ORAI1 proteins in the plasma membrane and activated by stromal interaction molecules 1 (STIM1) and STIM2 in the endoplasmic reticulum (ER). Mutations in ORAI1 and STIM1 genes that abolish SOCE cause severe immunodeficiency with recurrent infections due to impaired T cell function. SOCE has also been observed in cells of the innate immune system such as macrophages and dendritic cells (DC) and may provide Ca2+ signals required for their function. The specific role of SOCE in macrophage and DC function, and its contribution to innate immunity, however, is not well defined. We found that non-selective inhibition of Ca2+ signaling strongly impairs many effector functions of bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs) including phagocytosis, inflammasome activation, and priming of T cells. Surprisingly however, macrophages and DCs from mice with conditional deletion of Stim1 and Stim2 genes – and therefore complete inhibition of SOCE – showed no major functional defects. Their differentiation, FcR-dependent and independent phagocytosis, phagolysosome fusion, cytokine production, NLRP3 inflammasome activation and their ability to present antigens to activate T cells was preserved. Our findings demonstrate that STIM1, STIM2 and SOCE are dispensable for many critical effector functions of macrophages and DCs, which has important implications for CRAC channel inhibition as a therapeutic strategy to suppress pathogenic T cells while not interfering with myeloid cell functions required for innate immunity.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells

Vaeth

Zee

Concepcion

et al. 2015

The Journal of Immunology

Self Cite

102

View full text Add to dashboard Cite

show abstract

“…A similar reduction of IL-10 expression was not observed in Foxp3 + Treg cells isolated from the CNS of MOG-immunized Orai1 fl/fl Cd4-Cre mice, likely because Treg cells in the CNS are mainly nTreg cells that appear to be able to express IL-10 in the absence of ORAI1. Normal suppressive function was also observed in iTreg cells generated from CD4 + T cells of Stim1 fl/fl Cd4-Cre mice (48). Stim1 -deficient CD4 + T cells were, however, impaired in their differentiation into Foxp3 + iTreg cells in vitro and after adoptive transfer into lymphopenic host mice in vivo (48).…”

Section: Discussionmentioning

confidence: 96%

“…Normal suppressive function was also observed in iTreg cells generated from CD4 + T cells of Stim1 fl/fl Cd4-Cre mice (48). Stim1 -deficient CD4 + T cells were, however, impaired in their differentiation into Foxp3 + iTreg cells in vitro and after adoptive transfer into lymphopenic host mice in vivo (48). The different effects of Orai1 and Stim1 deletion on iTreg differentiation are likely due to the more profound SOCE defect in CD4 + T cells lacking STIM1 rather than qualitative differences in ORAI1 and STIM1 dependent signal transduction.…”

Section: Discussionmentioning

confidence: 96%

Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function

Kaufmann

Shaw

Kozhaya

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The function of CD4+ T cells is dependent on Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI proteins. To investigate the role of ORAI1 in pro-inflammatory Th1 and Th17 cells and autoimmune diseases, we genetically and pharmacologically modulated ORAI1 function. Immunization of mice lacking Orai1 in T cells with MOG peptide resulted in attenuated severity of experimental autoimmune encephalomyelitis (EAE). The numbers of T cells and innate immune cells in the CNS of ORAI1-deficient animals were strongly reduced along with almost completely abolished production of IL-17, IFN-γ and GM-CSF despite only partially reduced Ca2+ influx. In Th1 and Th17 cells differentiated in vitro, ORAI1 was required for cytokine production but not the expression of Th1- and Th17-specific transcription factors T-bet and RORγt. The differentiation and function of induced iTreg cells, by contrast, was independent of ORAI1. Importantly, induced genetic deletion of Orai1 in adoptively transferred, MOG-specific T cells was able to halt EAE progression after disease onset. Likewise, treatment of wild-type mice with a selective CRAC channel inhibitor after EAE onset ameliorated disease. Genetic deletion of Orai1 and pharmacological ORAI1 inhibition reduced the leukocyte numbers in the CNS and attenuated Th1/Th17 cell-mediated cytokine production. In human CD4+ T cells, CRAC channel inhibition reduced the expression of IL-17, IFN-γ and other cytokines in a dose-dependent manner. Taken together, these findings support the conclusion that Th1 and Th17 cell function is particularly dependent on CRAC channels, which could be exploited as a therapeutic approach to T cell-mediated autoimmune diseases.

show abstract

Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes

Srikanth

Woo

Sun

et al. 2017

Store-Operated Ca²⁺ Entry (SOCE) Pathways

View full text Add to dashboard Cite

Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway. Stimulation of TCRs triggers depletion of intracellular Ca store and, in turn, activates store-operated Ca entry (SOCE) to raise the intracellular Ca concentration. SOCE in T cells is mediated by the Ca release-activated Ca (CRAC) channels, which have been very well characterized in terms of their electrophysiological properties. Identification of STIM1 as a sensor to detect depletion of the endoplasmic reticulum (ER) Ca store and Orai1 as the pore subunit of CRAC channels has dramatically advanced our understanding of the regulatory mechanism of Ca signaling in T cells. In this review, we discuss our current understanding of Ca signaling in T cells with specific focus on the mechanism of CRAC channel activation and regulation via protein interactions. In addition, we will discuss the role of CRAC channels in effector T cells, based on the analyses of genetically modified animal models.

show abstract

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

Cited by 56 publications

References 89 publications

Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells

Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells

Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function

Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes

Contact Info

Product

Resources

About