Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells

Piper, Christopher; Rosser, Elizabeth C.; Oļeiņika, Kristīne; Nistala, Kiran; Krausgruber, Thomas; Rendeiro, André F.; Banos, Aggelos; Drozdov, Ignat; Villa, Matteo; Thomson, Scott; Xanthou, Georgina; Bock, Christoph; Stockinger, Brigitta; Mauri, Claudia

doi:10.1016/j.celrep.2019.10.018

Cited by 106 publications

(118 citation statements)

References 76 publications

(129 reference statements)

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“…Moreover, cells within this subset also expressed the CCL22 and CCL17 genes encoding Th2 and Treg-actracting chemokines 21,22 . Speci c expression of these two genes in IL-10-secretion Bregs was recently described in the context of antigeninduced arthritis in mice 47 . It is plausible that differentiated B cells within this subset also display suppressive capabilities and other functional characteristics of Bregs.…”

Section: Discussionmentioning

confidence: 95%

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

Cordero

King

Dogra

et al. 2020

Preprint

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The thymus is a central lymphoid organ responsible for the development of T cells. Here, we show that the thymus of human neonates also contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells (ASC) are comprised within a larger subset of B cells lacking expression of the complement receptors CD21 and CD35 and sharing the expression of signature genes defining mouse B1 B cells. Single-cell transcriptomic analyses supported the intrathymic differentiation of CD138+ plasma cells alongside other B cell subsets with distinctive molecular phenotypes. Neonatal thymic plasma cells also included clones reactive to pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

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Section: Discussionmentioning

confidence: 95%

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

Cordero

King

Dogra

et al. 2020

Preprint

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“…The amino acid sensing enzymes GCN2 and mTOR may both play a part in detecting IDO-mediated tryptophan depletion, signaling cell cycle arrest as well promoting the differentiation of CD4 + T cells into regulatory T cells (55)(56)(57). In addition, tryptophan catabolites have been shown to induce both regulatory T and B cells through activation of the aryl hydrocarbon receptor (AhR) (58)(59)(60). Enhanced AhR activity is associated with disease in autoimmune patients and preclinical models of disease, and AhR agonists have been shown to inhibit inflammation in models of inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses

et al. 2020

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Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function. Indeed, IDO2, like IDO1, is necessary for the differentiation of regulatory T cells in vitro . However, compared to IDO1, in vivo studies demonstrated a contrasting role for IDO2, with experiments in preclinical models of autoimmune arthritis establishing a proinflammatory role for IDO2 in mediating B and T cell activation driving autoimmune disease. Given their potentially opposing roles in inflammatory responses, interpretation of results obtained using IDO1 or IDO2 single knockout mice could be complicated by the expression of the other enzyme. Here we use IDO1 and IDO2 single and double knockout (dko) mice to define the differential roles of IDO1 and IDO2 in B cell-mediated immune responses. Autoreactive T and B cell responses and severity of joint inflammation were decreased in IDO2 ko, but not IDO1 ko arthritic mice. Dko mice had a reduction in the number of autoantibody secreting cells and severity of arthritis: however, percentages of differentiated T cells and their associated cytokines were not reduced compared to IDO1 ko or wild-type mice. These data suggest that autoreactive B cell responses are mediated by IDO2, while autoreactive T cell responses are indirectly affected by IDO1 expression in the IDO2 ko mice. IDO2 also influenced antibody responses in models of influenza infection and immunization with T cell-independent type II antigens. Taken together, these studies provide evidence for the contrasting roles IDO1 and IDO2 play in immune responses, with IDO1 mediating T cell suppressive effects and IDO2 working directly in B cells as a proinflammatory mediator of B cell responses.

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“…Recently, an increasing number of reports have elicited that AhR playes a critical role in the regulation of Th17 and Treg cell differentiation (12,32). Thus, we investigated whether AhR contributes to the Sema4D-mediated the balance of Th17/Treg cells, CD4 + T cells were transfected with siAhR in the presence of Sema4D under Th17-or Treg-polarizing conditions, and the expression levels of AhR and the AhR target gene CYP1A1 were measured.…”

Section: The Ahr Pathway Is Involved In Sema4d-mediated Th17 Cell Andmentioning

confidence: 99%

Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis

2020

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Objectives: Semaphorin 4D (Sema4D) is constitutively expressed on T cells and osteoclasts, and regulates T cell proliferation and bone remodeling. In addition, several studies have shown that Sema4D is involved in the pathogenesis of autoimmunity. We undertook this study to investigate the mechanism by which Sema4D affects the pathogenic progress of ankylosing spondylitis (AS). Methods: Soluble Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema4D were evaluated in CD4 + and CD19 + cells from the AS patients and healthy individuals. The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from CD4 + T cells were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor (AhR) agonistic effect of Sema4D was detected by analyzing the activation of downstream signaling pathways and target genes using Luciferase and EROD assay. Results: Levels of sSema4D were elevated in both serum from AS patients, and clinical features markers were correlated with serum sSema4D levels. Sema4D facilitated CD4 + T cells proliferation and Th17 cells differentiation and inhibited Treg cells differentiation by enhancing RORγt expression and reducing Foxp3 expression, with increasing expression and secretion of IL-17 and IL-22. It induced the expression and activity of AhR target gene CYP1A1 and XRE reporter activity via interaction with CD72. Conclusion: These findings indicate that Sema4D as a potent activator of T cells in the immune response contributes to the inflammation of AS by inducing imbalance in Th17 and Treg cell populations in an AhR-dependent manner, suggesting it is a crucial participant in AS pathogenesis.

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Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells

Cited by 106 publications

References 76 publications

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses

Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis

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