B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation

Abstract

Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-β1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-β1 expression in B cells (B–TGF-β1−/−) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG). In this model, B–TGF-β1−/− mice showed an earlier onset of neurologic impairment compared to their littermate controls. Exacerbated EAE susceptibility in B–TGF-β1−/− mice was associated with augmented CNS T helper (Th)1/17 responses. Moreover, selective B cell TGF-β1–deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-β1 can constrain Th1/17 responses through inhibition of APC activity. Collectively our data suggest that B cells can down-regulate the function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-β1, findings that may be relevant to B cell-targeted therapies.

Activation of human B cells negatively regulates TGF-β1 production

“…Strikingly, stimulation of B cells by engagement of BCR and TLR9 decreased TGF-β1 production. In regards to the implication of TGF-β1 expression in regulatory B cell functions in immune tolerance [36, 38, 55, 56], the present findings imply that loss of B cell-derived TGF-β1 production following B cell activation may confer increased susceptibility to autoimmune responses.…”

“…While initially all regulatory functions of suppresive B cells were attributed to their capabilities to produce IL-10, recent studies have highlighted additional mechanisms by which Bregs suppress immunity. In addition to the recently reported regulatory role of IL-35-producing B cells during disease recovery [61], data from our group have established that TGF-β1-producing B cells restrain the initiation phase of EAE and the development of Th17 cells [36]. Consistent with a regulatory role of B cell-derived of TGF-β1 production in CNS autoimmunity, B cells were previously found to have a central function in induction of oral tolerance and amelioration of EAE via the up-regulation of TGF-β in gut associated lymphoid tissue (GALT) [44, 62].…”

“…The characterization of human TGF-β1-producing B cells may provide a better understanding of their function and development. Interestingly, the quantification of TGF-β1 expression by B cells in EAE mice [36] indicate that murine TGF-β1-producing B cells do not belong to the CD1d hi CD5 + B10 subset [74] or CD138 + plasma cells, which have been shown to be the main source of IL-10 and IL-35 during disease development [61, 75]. …”

“…Decreased IL-10 production was seen upon B cell activation via CD40, or B cell receptor (BCR) in conjunction with CD40 [17], or Toll-like receptor (TLR)9 [21, 23], indicating a general alteration of B cell functions in MS rather than a defect in certain activation signaling pathways. Similar to IL-10-producing B cells [33–35], transforming growth factor (TGF)-β1-producing regulatory B cells have recently been shown by our group to restrain the initiation phase of experimental autoimmune neuroinflammation [36], making them potentially important in maintaining peripheral immune tolerance in organ-specific autoimmune disease such as MS. Consistent with this premise, recent evidence indicates that B cell subpopulations expressing TGF-β can control regulatory T cell induction, immune tolerance promotion, and/or innate and adaptive immune response suppression [37–50].…”

Self-reactive B cells in the GALT are actively curtailed to prevent gut inflammation

“…Pharmacological inhibition of TGF-β signaling by using an inhibitor specific to TGFβR1/R2 reversed these phenotypes, promoted the survival of self-reactive B cells in the gut, and led to expression of chemokines that allowed homing of self-reactive B cells to other peripheral tissues. The TGF-β signaling pathway is shown to have pleiotropic effects on B cells (33)(34)(35)(36)(37)(38)(39)(40). In mucosal tissues, TGF-β signaling is known to be crucial for IgA production, where it cooperates with CD40 ligand and other cytokine signals delivered by T cells to induce class switch recombination in B cells (37).…”