Thymic B cells promote thymus-derived regulatory T cell development and proliferation

Lu, Fangting; Yang, Wei; Wang, Yin‐Hu; Ma, Hongdi; Tang, Wei; Yang, Jingbo; Li, Liang; Ansari, Aftab A.; Lian, Zhe‐Xiong

doi:10.1016/j.jaut.2015.05.008

Cited by 53 publications

(49 citation statements)

References 59 publications

(59 reference statements)

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“…Reports suggest that B cells are involved in the tolerance response to self-antigens derived from the anterior chamber of the eye123 and thymus456 as well as foreign antigens from the mucosal route789. Adoptive transfer of B cells prevented the T cell-induced inflammatory bowel disease and also the chemical-induced colitis91011.…”

mentioning

confidence: 99%

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

Chien

Chen

et al. 2017

Sci Rep

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The role of B cells in the development of CD4+ regulatory T cells has been emphasized recently. Our previous studies have demonstrated that the antigen-presenting splenic B cells converted naïve CD4+CD25− T cells into CD4+CD25+Foxp3− T cells without additional cytokines or chemicals with regulatory activity and that referred to as Treg-of-B cells. The present study further showed that Treg-of-B cells increased the IL-10-producing population, and the expression of c-Maf, inducible T-cell co-stimulator (ICOS) as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) after repeated stimulation of B cells in a cell-cell contact-dependent manner. Long-term cultured Treg-of-B cells exerted IL-10 and CTLA4-mediated antigen-specific suppressive activity; moreover, the single antigen-specific Treg-of-B cells inhibited in a non-antigen-specific fashion. In conclusion, these results suggest that repeated stimulation of B cells induced IL-10-producing CD4+Foxp3− regulatory T cells in a contact-dependent manner and these Treg-of-B cells possess IL-10 and CTLA4-dependent suppressive function.

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mentioning

confidence: 99%

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

Chien

Chen

et al. 2017

Sci Rep

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“…Recent studies have indicated that thymic B cells, either developed within or having immigrated from the periphery, can also efficiently present self-peptides to immature T cells [19, 20], facilitating negative selection as well as T reg cell development [58]. Yamano et al showed that this conversion of peripheral B cells requires a CD40 signal and that thymic B cells also express TRAs modulated by AIRE [20].…”

Section: Discussionmentioning

confidence: 99%

Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases

Woo

Reifman

2017

PLoS ONE

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Autoimmune diseases occur when immune cells fail to develop or lose their tolerance toward self and destroy body’s own tissues. Both insufficient negative selection of self-reactive T cells and impaired development of regulatory T cells preventing effector cell activation are believed to contribute to autoimmunity. Genetic predispositions center around the major histocompatibility complex (MHC) class II loci involved in antigen presentation, the key determinant of CD4+ T cell activation. Recent studies suggested that variants in the MHC region also exhibit significant non-additive interaction effects. However, collective interactions involving large numbers of single nucleotide polymorphisms (SNPs) contributing to such effects are yet to be characterized. In addition, relatively little is known about the cell-type-specificity of such interactions in the context of cellular pathways. Here, we analyzed type 1 diabetes (T1D) and rheumatoid arthritis (RA) genome-wide association data sets via large-scale, high-performance computations and inferred collective interaction effects involving MHC SNPs using the discrete discriminant analysis. Despite considerable differences in the details of SNP interactions in T1D and RA data, the enrichment pattern of interacting pairs in reference epigenomes was remarkably similar: statistically significant interactions were epigenetically active in cell-type combinations connecting B cells to T cells and intestinal epithelial cells, with both helper and regulatory T cells showing strong disease-associated interactions with B cells. Our results provide direct genetic evidence pointing to the important roles B cells play as antigen-presenting cells toward CD4+ T cells in the context of central and peripheral tolerance. In addition, they are consistent with recent experimental studies suggesting that the repertoire of B cell-specific self-antigens in the thymus are critical to the effective control of corresponding autoimmune activation in peripheral tissues.

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“…It is well known that the capacity for the activation and proliferation of thymocytes is critical for their development in vivo [24,25]. We investigated the possible change in the activation and proliferation of CD4 + SP cells in miR-126 KD mice.…”

Section: Mir-126 Deficiency Altered the Activation And Proliferation mentioning

confidence: 99%

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

et al. 2018

Int Arch Allergy Immunol

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Background: MicroRNA-126 (miR-126), a distinct miRNA family member, has been reported to be involved in the development and function of some types of immune cells. However, the potential role of miR-126 in the development of CD4⁺ T cells remains to be elucidated. Objectives: To investigate the potential role of miR-126 in the development of CD4⁺ T cells in the thymus and explore its significance. Methods: The relative expression level of miR-126 in thymus CD4⁺ single-positive (SP) cells was detected by Real-Time PCR assay. The possible change in thymus tissue was assessed by histopathology. The total cell number of thymocytes and the expression of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67, in CD4⁺ SP cells were assessed by flow cytometric analysis. The expression of IRS-1 and related signaling pathways including Akt and Erk were determined by flow cytometric analysis. Results: Compared with that in wild-type (WT) mice, the total cell number of thymocytes in miR-126 knockdown (KD) mice increased significantly. Moreover, the proportion and absolute cell number of thymic CD4⁺ SP cells decreased significantly in miR-126 KD mice. Further analysis showed that the frequencies of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67 in CD4⁺ SP cells also changed significantly, respectively. Mechanism aspect, the expression level of IRS-1, a putative target of miR-126, increased significantly in CD4⁺ SP cells in miR-126 KD mice. Moreover, the expression levels of the signaling molecules phosphorylated (p)-Akt and p-Erk also changed significantly. Conclusions: Our work is the first to reveal a previously unknown role of miR-126 in the development of CD4⁺ SP cells in the thymus, which might ultimately benefit studies on development of thymocytes.

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Thymic B cells promote thymus-derived regulatory T cell development and proliferation

Cited by 53 publications

References 59 publications

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

Collective Genetic Interaction Effects and the Role of Antigen-Presenting Cells in Autoimmune Diseases

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

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