Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells

Journal of Biomedical Science, Nov 2017

Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4+Foxp3+ regulatory T cells, several subsets of Foxp3- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4+CD25- T cells into CD25+Foxp3- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Treg-of-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3+ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells.

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Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells

Chien and Chiang Journal of Biomedical Science Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells Chien-Hui Chien 1 Bor-Luen Chiang 0 1 0 Department of Medical Research, National Taiwan University Hospital , Taipei City 10002, Taiwan , Republic of China 1 Graduate Institute of Clinical Medicine, National Taiwan University , Taipei City 10048, Taiwan , Republic of China Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4+Foxp3+ regulatory T cells, several subsets of Foxp3- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4+CD25- T cells into CD25+Foxp3- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Tregof-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3+ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells. Regulatory T cells; Lymphocyte-activation gene 3; Programmed cell death protein 1; Inducible T-cell co-stimulator; Interleukin 10; Cytotoxic T lymphocyte-associated antigen-4; Treg-of-B cells Background Regulatory T cells are a therapeutic strategy for immune dysregulated diseases and a potential target for cancer immunotherapy. In addition to CD4+Foxp3+ regulatory T (Treg) cells, studies have emphasized the roles of CD4 +Foxp3- regulatory T cells, such as TGF-β-producing T helper 3 (Th3) cells, IL-10-producing type 1 regulatory T (Tr1) cells, and others. Accumulating evidence demonstrate that naïve B cells possess the ability to promote naïve CD4+ T cells into CD25+ Foxp3- regulatory T cells with the expression of lymphocyte activation gene-3 (LAG3, CD223), inducible co-stimulator (ICOS, CD278), programmed cell death protein 1 (PD1, CD279), and glucocorticoid-induced TNFR family-related protein (GITR). B-cell-induced CD4+Foxp3- regulatory T cells exert the inhibition through both IL-10-independent and cell-cell contact-dependent mechanisms, although they also show IL-10-mediated suppression. Furthermore, these B cell-induced regulatory T cells protect mice from several immune disorders, including graft-versus-host disease, experimental allergic asthma, collagen-induced Main text CD4+Foxp3+ regulatory T cells Sakaguchi et al. demonstrated that CD4+CD25+ T cells contributed to maintaining self-tolerance in a nonantigen-specific manner [ 1 ]. Immune dysregulation, polyendocrinophathy, enteropathy X-linked (IPEX) syndrome is a recessive immune disorder. Reports showed that IPEX is caused by mutations of FOXP3 gene, which is orthologouse of the Foxp3 gene mutated in scurfy mouse [ 2–4 ]. Further studies demonstrated that Foxp3 expressed predominantly in CD4+CD25+ T cells than CD4+CD25- T and CD19+ B cells. Moreover, retroviral transduction of Foxp3 in naïve CD4+CD25- T cells converted these cells toward Treg cells phenotype. Thus, Foxp3 has been identified as the master transcription factor of Treg cells [ 5 ]. Thymus-derived Foxp3+ regulatory T cells In addition to Foxp3, thymus-derived CD4+CD25+Foxp3 + regulatory T (tTreg) cells highly expressed Helios, cytotoxic T lymphocyte-associated antigen-4 (CTLA4, CD152), neuropilin-1, GITR, galectin-1, IL-10, and granzyme B [ 6 ]. tTreg cells could be activated in an antigenspecific fashion and exerted suppressive activity in a non-antigen-specific fashion [ 7 ]. tTreg cells produced many inhibitory cytokines, including TGF-β1, IL-10, and IL-35, to downregulate immune responses [ 8 ]. Furthermore, tTreg cells exhibited cell-cell contact-dependent suppression via latency-associated peptide (LAP) [ 9 ], CD39 (ectonucleoside triphosphate diphosphohydrolase1, ENTPD1) and CD73 (ecto-5′-nucleotidase) [ 10 ], and cytosolic cyclic adenosine monophosphate (cAMP) [ 11 ]. Reports showed that tTreg cells induced effector T cell apoptosis via various pathways, including deprivation of IL-2 and IL-7 [ 12 ], disruption of effector cell membrane integrity by granzyme B [ 13 ], galectin-1-induced apoptosis [ 14 ], and the engagement of TNF-related apoptosis inducing ligand (TRAIL)-death receptor 5 (DR5) [ 15 ]. Additionally, tTreg cells inhibited effector T cell activation via downregulation of costimulatory molecules on DCs through CTLA4 [ 16 ] and LAG3 [ 17 ]. These studies indicate that tTreg cells are a polyclonal population, and the above mentioned complicated mechanisms result in maximal immunosuppression during homeostasis. (...truncated)


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Chien-Hui Chien, Bor-Luen Chiang. Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells, Journal of Biomedical Science, pp. 86,