Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis

Chen, Xing; Ma, Ning; Xiao, He; Wang, Xiaoqian; Zheng, Mingke; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Shen, Beifen; Yan, Li; Wang, Renxi

doi:10.1189/jlb.3a0414-213rr

Cited by 54 publications

(42 citation statements)

References 64 publications

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“…However, in view of our data (Supporting Information Fig. 3D-F) showing that adoptive transfer of activated B cells depleted of p28, p35, or p40 also had minimal effects on pathogenic B cells and proteinuria, both of which are the hallmark features of SLE [21,22,[35][36][37][38], it is still justifiable to conclude that the IL-39 subunits impact disease much more so than other cytokine components. Taken together, our data suggest that IL-39, secreted by activated B cells, may be an important proinflammatory cytokine and the potential therapeutic target in lupus diseases.…”

Section: Discussionmentioning

confidence: 77%

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

et al. 2016

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Interleukin-12 family cytokines have emerged as critical regulators of immunity with some members (IL-12, IL-23) associated with disease pathogenesis while others (IL-27sue injury by promoting the expansion of regulatory B and T-cell subsets [2,3].Discovery of IL-23 in 2000 [4] led to the reevaluation of IL-12 and IL-23 in autoimmune diseases. For example, therapeutic targeting of IL-12p40 decreases pathology in many mouse models of autoimmune diseases [5], while disease is exacerbated in IL-12p35-deficient mice [6,7]. Thus, IL-23 rather than IL-12 was * These authors contributed equally to this work as first authors.* * These authors contributed equally to this work as senior authors. Eur. J. Immunol. 2016. 46: 1343-1350 found to be the critical cytokine for autoimmune inflammation including experimental immune-mediated disease [6][7][8][9][10]. Currently, at least ten therapeutic agents targeting IL-23 are being tested in the clinic for more than 17 human immune-mediated diseases [11]. Both IL-27 and IL-35 have immune-suppressive activities and are also cytokines with strikingly diverse influences on the immune response so that viable therapeutic targets may also be exploited for treatment of human inflammatory diseases [12,13]. Thus, understanding immunobiology of IL-12 family cytokines would undoubtedly provide valuable knowledge that can be exploited therapeutically. The IL-12 family cytokines are α/β heterodimers consisting of one α subunit (IL-23p19, IL-27p28, IL-12p35) and one β chain (IL-12p40, Ebi3) [14,15]. Although there are currently four known members in the family, the predictable range of combinations is six and it is conceivable that additional pairings such as IL-23p19/Ebi3 are possible [12,[14][15][16][17]. In this study, we sought to discover additional IL-12 members that might exist in nature. By combining different alpha and beta IL-12 subunit proteins in vitro we detected a novel stable p19/Ebi3 heterodimeric complex by immunoprecipitation. We have characterized the p19/Ebi3 cytokine (IL-39) and demonstrated that it possesses biological activities in vitro and in vivo. Results IL-23p19 (p19) and Ebi3 form a composite factor (IL-39)To examine whether p19 can form a stable complex with Ebi3, we mixed equal amounts of the two proteins and immunoprecipitation (IP)/Western blot analyses revealed formation of a stable human p19/Ebi3 complex (Fig. 1A). We could not detect the p19/Ebi3 following IP with isotype IgG or anti-c-Jun antibody, providing suggestive evidence for potential bona fide p19/Ebi3 cytokine. To confirm our finding in another animal species, we genetically engineered and expressed mouse p19 and Ebi3 subunits in CHO cells (Fig. 1B). IP of supernatants derived from transfectants with anti-p19 mAb and followed by Western blot analysis using anti-Ebi3 mAb confirmed coexpression p19 and Ebi3 and formation of a stable p19/Ebi3 heterodimer (Fig. 1C). We further confirmed this observation by reciprocal IP with anti-Ebi3 mAb and Western blotting with anti-p19 mAb and the p19/Ebi3 comple...

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Section: Discussionmentioning

confidence: 77%

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

et al. 2016

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“…A subset of CD5 + B cells have also been shown to be regulatory B cells, playing an important role in dampening several autoimmune pathologic conditions, such as collagen-induced arthritis, autoimmune encephalitis, chronic colitis among others (Matsushita et al, 2008; Yanaba et al, 2008). The ability of the CD5 + regulatory B cells in modulating immune responses and inflammation in autoimmune diseases is believed to be mediated by IL-10 (Xing et al, 2015; Yoshizaki et al, 2012). However, whether and how CD5 + B cells may dampen antitumor immune responses and/or enhance cancer-promoting inflammation remains to be explored.…”

Section: Introductionmentioning

confidence: 99%

CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

et al. 2016

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SUMMARY The participation of a specific subset of B cells and how they are regulated in cancer is unclear. Here, we demonstrate that the proportion of CD5+ relative to interleukin-6 receptor α (IL-6Rα) expressing B cells was greatly increased in tumors. CD5+ B cells responded to IL-6 in the absence of IL-6Rα. IL-6 directly bound to CD5, leading to activation of the transcription factor STAT3 via gp130 and its downstream kinase JAK2. STAT3 upregulated CD5 expression, thereby forming a feed-forward loop in the B cells. In mouse tumor models, CD5+ but not CD5−B cells promoted tumor growth. CD5+ B cells also showed activation of STAT3 in multiple types of human tumor tissues. Thus, our findings demonstrate a critical role of CD5+ B cells in promoting cancer.

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“…Thymic B cells are unique from peripheral B cells in that they express high levels of MHC class II and various co-stimulatory molecules. Several reports suggest that thymic B cells are required for deletion and Treg cell selection (summarized in (141)) by providing co-stimulation via CD5-CD72 (142) or CD40-CD40L (49, 50, 141, 143), or by MHC-dependent interactions (50, 141, 144). Studies of a BCR transgenic specific for GPI showed that thymic B cells acquire this circulating self-antigen and delete cognate specific TCR transgenic cells (140) (Figure 2).…”

Section: Bm-derived Apc Subsetsmentioning

confidence: 99%

Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen

Perry

Hsieh

2016

Immunological Reviews

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The development of T cell self-tolerance in the thymus is important for establishing immune homeostasis and preventing autoimmunity. Here, we review the components of T cell tolerance, which includes TCR self-reactivity, costimulation, cytokines, and antigen presentation by a variety of APCs subsets. We discuss the current evidence on the process of regulatory T (Treg) cell and negative selection and the importance of TCR signaling. We then examine recent evidence showing unique roles for bone marrow (BM)-derived APCs and medullary thymic epithelial cells (mTECs) on the conventional and Treg TCR repertoire, as well as emerging data on the role of B cells in tolerance. Finally, we review the accumulating data that suggest that cooperative antigen presentation is a prominent component of T cell tolerance. With the development of tools to interrogate the function of individual APC subsets in the medulla, we have gained greater understanding of the complex cellular and molecular events that determine T cell tolerance.

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Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis

Abstract: This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19 + CD5

Cited by 54 publications

References 64 publications

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

A novel IL‐23p19/Ebi3 (IL‐39) cytokine mediates inflammation in Lupus‐like mice

CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer

Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen

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