CD4+ and CD8+ T cell–dependent antiviral immunity requires STIM1 and STIM2

Shaw, Patrick J.; Weidinger, Carl; Vaeth, Martin; Luethy, Kevin; Kaech, Susan M.; Feske, Stefan

doi:10.1172/jci76602

Cited by 50 publications

(66 citation statements)

References 86 publications

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“…+ T cells (in these cells all NFAT activity is abolished) and almost normal tumor reactivity of Stim1 −/− or Stim2 −/− CD8 + T cells (with slightly reduced NFAT activity), whereas CD4 + T cells of these mice have a clear cytokine defect (31,32).…”

Section: Cd8mentioning

confidence: 95%

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Vaeth

Bäuerlein

Pusch

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3+ regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8+ T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

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Section: Cd8mentioning

confidence: 95%

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Vaeth

Bäuerlein

Pusch

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…T cell-specific deletion of Stim1/Stim2 results in increased susceptibility to acute viral infection with lymphocytic choriomeningitis virus (LCMV) (3) and impaired antitumor immunity (4) due to perturbed CD8 + T cell effector functions. Furthermore, both CD4 + and CD8 + T cells require SOCE mediated by STIM1/STIM2 to sustain memory CD8 + T cell response to acute viral infection (3). Patients (PATs) with inherited mutations in ORAI1 or STIM1 genes that abolish SOCE develop a SCID-like disease termed CRAC channelopathy (5,6).…”

Section: +mentioning

confidence: 99%

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

Desvignes¹,

Weidinger²,

Shaw³

et al. 2015

J. Clin. Invest.

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“…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%

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

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105

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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.

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CD4+ and CD8+ T cell–dependent antiviral immunity requires STIM1 and STIM2

Cited by 50 publications

References 86 publications

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

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

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

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