Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells

Sekiya, Takashi; Kondo, Taisuke; Shichita, Takashi; Morita, Rimpei; Ichinose, Hiroshi; Yoshimura, Akihiko

doi:10.1084/jem.20142088

Cited by 59 publications

(73 citation statements)

References 54 publications

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“…Notably, scurfy mice and IPEX patients both develop hyper-IgE syndrome and eosinophilia. A dominant Th2 response was also observed in Foxp3-deficient mice (69) and in mice with Treg cell-specific deletion of CTLA-4 (62), ITCH (113), IRF4 (69), CK2 (86), or Nr4a (114), suggesting that these molecules expressed on Treg cells are involved in the control of Th2 responses. However, the mechanisms that link the loss of Treg cell function to the allergic Th2-type responses are not fully understood (115–119).…”

Section: Discussionmentioning

confidence: 96%

“…While numerous signaling pathways can account for the resistance phenotype (122), one relevant to Th2 cell resistance might involve IL-4 signaling and STAT6 activation, as previously documented in vitro (132) and in vivo (133). Whether this lack of susceptibility to Treg cell-mediated suppression is also associated with the preferential reduction of other Treg cell subsets that regulate Th2 cells (86, 113, 114), the absence of gastric antigen-specific Treg cells among the rebounded Treg cells (34, 134), or additional possibilities (135) remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

Harakal

Rival

Qiao

et al. 2016

The Journal of Immunology

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Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6 DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient Treg cell depletion results in long-lasting AIG associated with both H+K+ATPase and intrinsic factor autoantibody responses. Although functional Treg cells emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg cell-mediated suppression. While previous studies have implicated dysregulated Th1 responses in AIG pathogenesis, eosinophils have been detected in gastric biopsies from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach draining lymph nodes. Additionally, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IRF4+PD-L2+ dendritic cells and ILT3+ rebounded Treg cells were detected after transient Treg cell depletion. Collectively, these data suggest that Treg cells maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in autoimmune gastritis.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

Harakal

Rival

Qiao

et al. 2016

The Journal of Immunology

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“…Since we find that these same genes are under tonic LAT-HDAC7 control in naïve CD4 + T cells, this suggests that tonic LAT-HDAC7 signals may also regulate this gene set in T REG . Furthermore, Nur77 and the two other Nr4a family members are critical for the generation of T REG (Sekiya et al, 2013) and suppression of T H 2 by T REG (Sekiya et al, 2015) and Irf4 was shown to have a T REG -intrinsic role to suppress T H 2 differentiation as well (Zheng et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

et al. 2017

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Summary CD4+ T cells differentiate into T helper cell subsets in feed-forward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naïve CD4+ T cells avoid spontaneous engagement of feed-forward mechanisms but retain a prepared state. T cells lacking the adapter molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4+ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4+ T cell proliferation and uncover a suppressive role for Irf4 in TH2 polarization; halving Irf4 gene-dosage leads to increases in GATA3+ and IL4+ cells. Our studies reveal that naïve CD4+ T cells are dynamically tuned by tonic LAT-HDAC7 signals.

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“…Previous studies have identified components of the transcriptional network supporting Treg differentiation and functions. These include factors enabling Foxp3-mediated gene expression (64), factors enforcing Foxp3 expression and Treg fitness, including Gata3 (65, 66), Nur77-family members (67–69), the chromatin modifier Ezh2 (70), or the pathway activated by PI-3 kinase activity and targeting Foxo transcription factors and the metabolic regulator mTOR (reviewed in 71, 72). Our study supports the conclusion that the main function of Thpok and LRF in post-thymic Tregs is to support Foxp3-mediated gene expression rather than to maintain expression of Foxp3 itself.…”

Section: Discussionmentioning

confidence: 99%

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

Carpenter

Wohlfert

Chopp

et al. 2017

The Journal of Immunology

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The CD4+-lineage specific transcription factor Thpok is required for intrathymic CD4+ T cell differentiation and, together with its homolog LRF, supports CD4+ T cell helper effector responses. However, it is not known if these factors are needed for the T regulatory (Treg) arm of MHC-II responses. Here, by inactivating in mice the genes encoding both factors in differentiated Tregs, we show that Thpok and LRF are redundantly required to maintain the size and functions of the post-thymic Treg pool. They support IL 2-mediated gene expression and the functions of the Treg-specific factor Foxp3. Accordingly, Treg-specific disruption of Thpok and Lrf causes a lethal inflammatory syndrome similar to that resulting from Treg deficiency. Unlike in conventional T cells, Thpok and LRF functions in Tregs are not mediated by their repression of the transcription factor Runx3. Additionally, we found Thpok needed for the differentiation of thymic Treg precursors, an observation in line with the fact that Foxp3+ Tregs are CD4+ cells. Thus, a common Thpok-LRF node supports both helper and regulatory arms of MHC-II responses.

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Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells

Abstract: Sekiya et al. demonstrate that deletion of the nuclear orphan receptor Nr4a in T reg cells results in a fatal systemic immunopathology due to abrogated suppressive capability in limiting Th2 and Tfh conversion.

Cited by 59 publications

References 54 publications

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

Control of Regulatory T Cell Differentiation by the Transcription Factors Thpok and LRF

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