NFAT control of immune function: New Frontiers for an Abiding Trooper

Vaeth, Martin; Feske, Stefan

doi:10.12688/f1000research.13426.1

Cited by 162 publications

(139 citation statements)

References 123 publications

(200 reference statements)

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“…The decreased NFAT levels might lead to the altered Treg cells profile by further affecting the NFAT:FOXP3 complex formation (Figure ). In induced Tregs (iTregs), NFATs regulate the expression of FOXP3 by binding to the Cis‐regulatory element of FOXP3 CNS1 (Vaeth & Feske, ). Studies with double‐deficient NFAT mouse models ( NFAT 1, 2, and 4 knockout mice) also reported a diminished FOXP3 expression by iTregs (Kwon et al, ; Vaeth et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The NFAT:FOXP3 complex regulates the Treg function by upregulating the expression of suppressive genes like CTLA4, IL10, TGFB, and downregulating the expression of IL2 and IL4. However, the disruptive mutations and the altered levels of NFAT:FOXP3 complex lead to non‐functional Tregs (Figure ) (Vaeth & Feske, ). Since we found decreased expression of both NFATs and FOXP3, we further assessed their effect on downstream immune‐suppressive genes in Tregs of GV patients.…”

Section: Discussionmentioning

confidence: 99%

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Altered expression of nuclear factor of activated T cells, forkhead box P3, and immune‐suppressive genes in regulatory T cells of generalized vitiligo patients

Giri

Dwivedi

Laddha³

et al. 2020

Pigment Cell Melanoma Res

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The study was aimed to analyze expression of nuclear factor of activated T cells (NFATs), forkhead box P3 (FOXP3), and their associated genes (sCTLA4, flCTLA4, IL10, TGFB, IL2, IL4, CD25) in regulatory T cells (Tregs) of 48 generalized vitiligo (GV) patients and 45 unaffected controls. The transcripts of NFATC1 to NFATC4, FOXP3, IL10, flCTLA4 (p < .0001), NFAT5 (p = .0003), sCTLA4 (p = .001), and FOXP3 protein in Tregs and plasma IL‐10 levels were reduced significantly (p < .0001) in GV Tregs compared to controls. The FOXP3 promoter polymorphisms [rs3761548(C > A), rs3761547(A > G), and rs2232365(A > G)] revealed significantly decreased FOXP3 protein levels in patients' Tregs with susceptible AA, GG, and GG genotypes (p < .0001, p = .028, p = .022, respectively). The active vitiligo Tregs showed reduced levels of NFATC3, NFATC4, NFAT5, FOXP3, TGFB, and flCTLA4 transcripts (p = .0005, p = .0003, p = .0002, p = .020, p < .0001, p = .006, respectively) and FOXP3 and TGF‐β proteins (p = .0394 and p = .0013) compared to stable vitiligo. Early‐onset patients (1–20 years) demonstrated decreased IL‐10, sCTLA‐4, flCTLA‐4, TGFB, and FOXP3 transcripts and FOXP3 protein as compared to late‐onset patients (41–60 years) (p = .001, p = .003, p = .009, p = .005, p = .038, p = .0226, respectively). Overall, our results for the first time suggest a likely role of NFATs and FOXP3 together with Treg immune‐suppressive genes in GV pathogenesis and disease progression, warranting additional investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Altered expression of nuclear factor of activated T cells, forkhead box P3, and immune‐suppressive genes in regulatory T cells of generalized vitiligo patients

Giri

Dwivedi

Laddha³

et al. 2020

Pigment Cell Melanoma Res

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“…Creation of the congenic SHR-A3(Stim1-B2) line demonstrates that rescue of defective Stim1 function prevents development of cerebrovascular disease in SHR-A3 while restoring T helper cell functions. Stim deficiency limits the ability of T helper cells to provide effective help to B cells as the latter undergo antibody affinity maturation [16,36]. This results in premature termination of affinity maturation and the development of antibody-secreting cells that generate self-reactive antibodies.…”

Section: Discussionmentioning

confidence: 99%

Natural genetic variation in Stim1 creates stroke in the spontaneously hypertensive rat

et al. 2020

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Similar to humans, the risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study, we show the involvement of genetic variation affecting the store-operated calcium signaling gene, Stim1, in the pathogenesis of stroke in SHR. Stim1 is a key lymphocyte activation signaling molecule and contains functional variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which Stim1 was substituted with the corresponding genomic segment from SHR-B2. Compared with SHR-A3 rats, Stim1 congenic SHR-A3 (SHR-A3(Stim1-B2)) have reduced cerebrovascular disease in response to salt loading including lower neurological deficit scores and cerebral edema. Microbleeds and major hemorrhages occurred in over half of SHR-A3 rats. These lesions were absent in SHR-A3(Stim1-B2) rats. Loss of Stim1 function in mice and humans is associated with antibody-mediated autoimmunity due to defects in T lymphocyte helper function to B cells. We investigated autoantibody formation using a high-density protein array to detect the presence of IgG and IgM autoantibodies in SHR-A3. Autoantibodies to key cerebrovascular stress proteins were detected that were reduced in the congenic line.

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“…Although the best understood functions of CN in mammals are in regulation of the immune system (Hogan et al, 2003;Vaeth and Feske, 2018), recent evidence suggests it also plays a part in the stress response (Medina et al, 2015;Zhang et al, 2016). Oxidative stress and nutrient limitation both lead to the release of intracellular Ca 2+ stores that activate CN.…”

Section: Discussionmentioning

confidence: 99%

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

et al. 2019

Preprint

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Upon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between diverse stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the stress-activated phosphatase calcineurin (CN) in this process and show that CN utilizes multiple pathways to control the cell cycle. Upon activation, CN inhibits transcription factors (TFs) that regulate the G1/S transition through activation of the stress-activated MAPK Hog1. In contrast, CN inactivates G2/M TFs through a combination of Hog1-dependent and -independent mechanisms. These findings demonstrate that CN and Hog1 act in a coordinated manner at multiple nodes of the cell cycle-regulatory network to rewire gene expression and arrest cells in response to stress. Our results suggest that crosstalk between CN and stress-activated MAPKs helps cells tailor their adaptive responses to specific stressors.

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NFAT control of immune function: New Frontiers for an Abiding Trooper

Cited by 162 publications

References 123 publications

Altered expression of nuclear factor of activated T cells, forkhead box P3, and immune‐suppressive genes in regulatory T cells of generalized vitiligo patients

Altered expression of nuclear factor of activated T cells, forkhead box P3, and immune‐suppressive genes in regulatory T cells of generalized vitiligo patients

Natural genetic variation in Stim1 creates stroke in the spontaneously hypertensive rat

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

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