NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells

Bopp, Tobias; Palmetshofer, Alois; Serfling, Edgar; Heib, Valeska; Schmitt, Steffen; Richter, Christoph; Klein, Matthias; Schild, Hansjörg; Schmitt, Edgar; Stassen, Michael

doi:10.1084/jem.20041538

Cited by 130 publications

(125 citation statements)

References 27 publications

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“…This small TCR derived Ca 2+ response is significantly enhanced in the absence of CD5 suggesting that TCR generates better signals in T reg cells in the absence of CD5 and thus may contribute to their greater effectiveness. A role for calcium elevation in T reg function is supported by the finding that NFAT transcription factor is important for T reg cell function (41). There are reports suggesting that an interaction between NFAT and Foxp3 is required for the effector function of T reg cells (42)(43)(44)(45).…”

Section: Discussionsupporting

confidence: 49%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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Section: Discussionsupporting

confidence: 49%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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“…In contrast to the established role of Ca 2+ , previous data revealed that nTreg in mice deficient for NFAT1 plus NFAT4 were neither decreased in number nor impaired in their suppressive capacity (14). Therefore, it was concluded that NFAT2 might be the important family member for controlling nTreg development and/or function (10).…”

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confidence: 77%

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells

Vaeth

Schliesser

Müller

et al. 2012

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

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Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ability of CD4 + T cells to differentiate into iTreg diminished markedly with the number of NFAT family members missing. It can be concluded that the expression of Foxp3 in TGF-β-induced iTreg depends on the threshold value of NFAT rather than on an individual member present. This is specific for iTreg development, because frequency of nTreg remained unaltered in mice lacking NFAT1, NFAT2, or NFAT4 alone or in combination. Different from expectation, however, the function of both nTreg and iTreg was independent on robust NFAT levels, reflected by less nuclear NFAT in nTreg and iTreg. Accordingly, absence of one or two NFAT members did not alter suppressor activity in vitro or during colitis and transplantation in vivo. This scenario emphasizes an inhibition of high NFAT activity as treatment for autoimmune diseases and in transplantation, selectively targeting the proinflammatory conventional T cells, while keeping Treg functional.gene regulation | tolerance | autoimmunity

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“…Therefore, NFAT/ICER complexes seem to be instrumental for the transcriptional attenuation of numerous NFAT-driven cytokine promoters in conventional CD4 + T cells. A critical role of NFAT factors for inhibitory complex formation is further strengthened by observations indicating that combined NFATc2/c3 deficiency rendered conventional CD4 + T cells unresponsive to suppression, although normal nTreg development was detected in those mice (11). Moreover, targeting ICER/ CREM in RNAi and antisense RNA approaches antagonized the nTreg-mediated suppression and/or inhibition of IL-2 production in conventional CD4 + T cells, rendering these effector T cells refractory to suppression (7,12).…”

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confidence: 86%

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

Vaeth¹,

Gogishvili

Bopp

et al. 2011

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

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Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3′ region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4 + T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4 + T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMPdriven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/ CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/ CREM and inhibition of NFATc1 and IL-2 induction.adenosin 3′,5′-cyclic monophospate | transcription | lymphocytes

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NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells

Cited by 130 publications

References 27 publications

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

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NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells

Cited by 130 publications

References 27 publications

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

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Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells