The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

Jana, Swapan Kumar; Jailwala, Parthav; Haribhai, Dipica; Waukau, Jill; Glišić, Sanja; Grossman, William; Mishra, Manoj K.; Wen, Renren; Wang, Demin; Williams, Calvin B.; Ghosh, Soumitra

doi:10.1002/eji.200939201

Cited by 44 publications

(38 citation statements)

References 55 publications

(82 reference statements)

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“…Preservation of IL-17A + CD4 + T cell development with decreased FoxP3 + CD4 + T cell generation during in vitro polarization of CD4-Cre;Smad4 fl/fl T cells has been noted previously (59). Interestingly, iTreg generation also requires Smad3, in addition to TGF-β-induced ERK and JNK activation, although the requirement for Smad3 in iTreg versus Th17 polarization appears to vary (81)(82)(83). In vivo, no defect in Foxp3 transcripts was observed in experimental animals versus controls.…”

Section: Ifn-γ-and Il-4-encoding Transcripts Indicative Of Th1 Andmentioning

confidence: 66%

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Hahn¹,

Falck²,

Jirik³

2011

J. Clin. Invest.

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While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-β signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-β, IL-1β, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A + CD4 + T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-β-mediated in vitro polarization of FoxP3 + CD4 + T cells, but not IL-17A + CD4 + T cells, suggesting that the epithelial lesions may have arisen as a consequence of unchecked Th17 cell activity. Proinflammatory cytokine production likely accounted for the raised levels of IL-11, a cytokine known to promote gastric epithelial cell survival and hyperplasia. Consistent with IL-11 having a pathogenic role in this model, we found evidence of Stat3 activation in the gastric polyps. Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region.

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Section: Ifn-γ-and Il-4-encoding Transcripts Indicative Of Th1 Andmentioning

confidence: 66%

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Hahn¹,

Falck²,

Jirik³

2011

J. Clin. Invest.

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“…For example, individuals with functional defects in STIM or Ca 2ϩ release-activated Ca 2ϩ /Orai are profoundly immune-deficient, and mice conditionally lacking STIM in T lymphocytes develop autoreactive disorders in part because of defective thymic natural regulatory T cell induction by highaffinity self-agonists (70). A similar and selective defect in natural regulatory T cell development occurs in mice selectively lacking either c-Rel (71)(72)(73)(74)(75)(76) or upstream mediators of NF-B activation, including BCL10, PKC, CARMA1, CnA␤, and IKK␤ (77)(78)(79)(80)(81). Although our study focuses on p65-dependent transcriptional activation, the dual sensitivity of proximal and distal Ca 2ϩ signals we identified and the role of c-Rel in natural regulatory T cell development raises the intriguing possibility that c-Rel transcriptional activation is also Ca 2ϩ -dependent.…”

Section: Discussionmentioning

confidence: 99%

T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

Liu

Berry

Ruthel

et al. 2016

Journal of Biological Chemistry

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T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca2؉ to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-B. 2؉ -dependent checkpoint in TCR-induced NF-B signaling that has broad implications for the control of immune cell development and T cell functional specificity. Activation of T cells following antigen binding to the T cell antigen receptor (TCR)3 induces diverse lineage-and fate-specific proinflammatory and immune-modulatory responses. Central to these responses is the induction of quantitatively distinct intracellular Ca 2ϩ signals and their selective activation of the key transcription factors NFAT and NF-B (1-6). The mechanism by which Ca 2ϩ controls NFAT activation in lymphocytes is well established (7). In contrast, although Ca 2ϩ has been implicated in TCR-induced NF-B signaling (8 -10), how Ca 2ϩ regulates NF-B activity is largely unexplored and represents a significant gap in our understanding of transcriptional control of T cell development, activation, and functional specificity.In resting T cells, classical NF-B consists of heterodimers of p50/p65 or p50/c-Rel that are retained in the cytosol by members of the inhibitory family of IB proteins (11, 12). Following TCR engagement, IB kinase (IKK)-mediated phosphorylation triggers the ubiquitination and proteasomal degradation of IB␣, releasing p50/p65 and p50/c-Rel, which localize to the nucleus to initiate transcription of crucial immune-regulatory, proinflammatory, and proproliferative genes (13-30). Although TCR-mediated Ca 2ϩ mobilization has been implicated in proximal steps of NF-B activation (8 -10), the precise mechanisms and source of Ca 2ϩ that regulate nuclear localization and transcriptional activation of NF-B are poorly defined. It is well established that TCR signaling induces inositol 1,4,5-trisphosphate-mediated depletion of Ca 2ϩ from the endoplasmic reticulum (ER). A resulting Ca 2ϩ dissociation from the ER membrane protein stromal interaction molecule 1 (STIM1) triggers its oligomerization and relocalization to ER membrane domains juxtaposed to the plasma membrane (31-33), where STIM1 physically gates Orai (also known as Ca 2ϩ release-activated Ca 2ϩ ) channels, allowing extracellular Ca 2ϩ to enter the cell (34,35). However, it is not known whether Ca 2ϩ control of TCR-induced NF-B signaling requires STIM1-and Orai1-mediated Ca 2ϩ influx or whether the initial release of Ca 2ϩ from the ER is sufficient for classical NF-B activation.In this study, we sought to determine both the source and mechanism of Ca 2ϩ control of antigen receptor-induced NF-B activation in T cells. We show that influx of extracellular Ca 2ϩ via STIM1 and Orai is critical for TCR-but not TNFinduced IB␣ degradation and NF-B activation. Importantly, we also demonstrate that Ca 2ϩ -dependent, PKC␣-mediated phosphorylation of p65 critically regulates its nuclear localization and transcriptional activation following TCR engagement. Thus, our findings ...

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“…However, the CYLD ko mice we analyzed (29) did not show signs of defect in T cell development as their CD4 + and CD8 + SP thymocyte numbers were comparable to those of WT mice. NFkB signaling has also been implicated in the development and regulation of Tregs (10)(11)(12)(37)(38)(39) (41,42), pointing to a different regulatory mechanism driving the expression of Foxp3. When we investigated the suppressive capacity of CYLD ex7/8 Tregs in vivo, we found that these cells were not able to suppress effector T cell function.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells

Reißig

Hövelmeyer

Weigmann

et al. 2012

The Journal of Immunology

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CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. We have previously described a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLDex7/8). In this study, we demonstrate that CYLD plays a critical role in Treg development and function. T cells of CYLDex7/8 mice had a hyperactive phenotype manifested by increased production of inflammatory cytokines and constitutive activation of the NF-κB pathway. Furthermore, the amount of Foxp3+ regulatory T cells in these mice was markedly enhanced in thymus and peripheral organs. Importantly, these regulatory T cells displayed decreased expression levels of CD25 and CTLA-4 associated with impaired suppressive capacity. Hence, our data emphasize an essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses.

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The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

Cited by 44 publications

References 55 publications

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry

The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells

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