Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells

Chang, Jae Hoon; Xiao, Yichuan; Hu, Hongbo; Jin, Jin; Yu, Jiayi; Zhou, Xiaofei; Wu, Xuefeng; Johnson, Howard M.; Akira, Shizuo; Pasparakis, Manolis; Cheng, Xuhong; Sun, Shao Cong

doi:10.1038/ni.2267

Cited by 117 publications

(135 citation statements)

References 44 publications

(92 reference statements)

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“…According to our hypothesis, we observed a differential polyubiquitination profile distinguished by a decreased expression of K63 substrates in lupus T regs , but not in effector T cells. This is in agreement with Chang and colleagues, who stated that E2 ubiquitin-conjugating enzyme Ube2n, which is the only enzyme that specifically promotes K63-polyubiquitination [40], seems to be crucial for stability and immunosuppressive in-vivo function of T regs in murine models [46]. Taken together, there is strong evidence to support that there are several defects in the ubiquitination profile of T regs from patients with SLE which contribute to resistance to suppression, a phenomenon that is not confined to effector T cell abnormalities.…”

Section: Discussionsupporting

confidence: 80%

“…However, the role of ubiquitination in resistance to suppression phenotype in SLE has not been defined completely. Although many studies have suggested that resistance to suppression in SLE is due to an effector T cell resistance and not to an abnormal regulatory function [15,16], it has been demonstrated that this subpopulation displays some molecular defects which could be associated with the acquisition of an effector phenotype [46,47].…”

Section: Discussionmentioning

confidence: 99%

“…Our results are consistent with this notion, and imply that increased STAT-3 phosphorylation in T regs is the hallmark of resistance to suppression in SLE. Moreover, in Ubc13-deficient T regs there is a reduced expression of suppressor of cytokine signalling-1 (SOCS1), which contributes to T reg stability by repressing the output of proinflammatory cytokine receptors, and particularly favours STAT molecule degradation [46]. Finally, it is well known that Ubc13 expression is down-regulated by STAT-3 operating as a transcriptional repressor of the Ube2n gene and modulating nuclear factor kappa B (NF-jB) activity, which seems to be crucial for T reg stability and prevention of their conversion into effector-like T cells [54].…”

Section: Discussionmentioning

confidence: 99%

“…As Ubc13 inducible knock-out mice specific for T regs display a reminiscent pathological phenotype of the T reg -deficient mice [46], we hypothesized that Cbl-b deficiency would modify the ubiquitin profile of T regs from SLE patients in a K63-dependent manner, which could contribute to resistance to suppression. We analysed Lys63 (K63) expression by Western blotting in CD4 1 CD25 1 T reg lysates from SLE patients compared to healthy controls.…”

Section: Cd25mentioning

confidence: 99%

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Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Romo-Tena

Aparicio‐Vera

Alcocer‐Varela

et al. 2017

Clinical and Experimental Immunology

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Summary T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4+CD25–) and regulatory (CD4+CD25+) T cells (Tregs) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in Tregs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in Tregs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus Tregs. In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of Tregs in lupus patients.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cd25mentioning

confidence: 99%

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Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Romo-Tena

Aparicio‐Vera

Alcocer‐Varela

et al. 2017

Clinical and Experimental Immunology

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“…[13][14][15][16][17][18][19][20][21] In addition, conditional UBC13 knockout (KO) studies revealed that the UBC13-IKK signaling axis regulates the function of Treg cells and prevent their conversion into inflammatory T cells. 22 In addition to mediating IKK activation, TAK1 targets the activation of MAP kinases, including ERK, p38, and JNK. [23][24][25] TAK1 transduces signals from multiple immune receptors, including the toll-like receptors (TLRs), TCR, B-cell receptor (BCR), and TNF receptor (TNFR) superfamily members.…”

Section: Introductionmentioning

confidence: 99%

Survival and maintenance of regulatory T cells require the kinase TAK1

Chang

Sun

2015

Cell Mol Immunol

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Regulatory T (Treg) cells play a central role in regulating peripheral immune tolerance and preventing autoimmunity. Despite the extensive studies on the development of Treg cells, the molecular mechanisms that maintain the population of committed Treg cells remain poorly understood. We show here that Treg-conditional ablation of the kinase TAK1 reduced the number of Treg cells in the peripheral lymphoid organs, causing abnormal activation of conventional T cells and autoimmune symptoms. Using an inducible gene knockout approach, we further demonstrate that TAK1 is crucial for the survival of Treg cells. Expression of a constitutively active IkB kinase partially restored the level of Treg cells in the TAK1Treg-KO mice. These results suggest a crucial role for TAK1 for maintaining the survival of committed Treg cells under physiological conditions.

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AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF‐β receptor II signaling

Liu

Sun

et al. 2013

Eur J Immunol

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The generation of CD4 + Foxp3 + Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-β receptor 2 (Tgfbr2 −/− mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4 + Foxp3 + Treg cells before they egressed to peripheral tissues. CD4 + Foxp3 + thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2 −/− Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2 −/− Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-β signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.Keywords: AKT r Stability r TGF-β r Thymus r Treg cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural CD4 + CD25 + Treg cells play an important role in maintaining self-tolerance and preventing autoimmune diseases and inflammation [1][2][3][4]. Treg cells are produced mainly in the thymus and express the transcription factor Foxp3, which is essential for the generation and regulatory function of Treg cells [5][6][7][8].CD4 + Foxp3 + Treg cells are heterogeneous in the phenotype and function under certain pathogenic conditions. Treg cells can Correspondence: Prof. Yongzhong Liu e-mail: liuyzg@shsci.org adjust themselves appropriately in the transcriptional program of T-effector (Teff) cell-related molecules in different inflammatory settings, to optimize the selective suppression of T cells [9][10][11]. Several studies have shown that together with alterations of Foxp3 expression, Treg cells have the potential for conversion to Th1, Th2, Th17 Teff cells as well as follicular helper T cells, and that the diversity in functional Treg-cell reprogramming may depend on the different types of inflammation [6,[12][13][14][15][16][17][18][19][20][21]. Recent studies demonstrate that Foxp3 + Treg cells can be converted to IFN-γ-producing cells or IL-17-producing cells even without loss of Foxp3 expression [22][23][24][25][26]. The heterogeneity of Treg cells is actively debated and is important for the immune homeostasis and development of diseases. By tracking the fate of Treg cells in vivo, Rubtsov et al. [27] 522Yun Liu et al. Eur. J. Immunol. 2014. 44: 521-532 both physiologic and inflammatory conditions. Miyao et al...

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Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells

Cited by 117 publications

References 44 publications

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Survival and maintenance of regulatory T cells require the kinase TAK1

AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF‐β receptor II signaling

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