Resting B cells expand a CD4⁺CD25⁺Foxp3⁺ Treg population via TGF‐β3

Abstract

Regulatory T cells (Treg) play critical roles in maintaining tolerance and preventing autoimmunity. It is not fully clear how these cells are generated and maintained. Here, we show that resting B cells are able to expand Treg. This expansion requires TGF-b3 and signaling through the TCR and CD28. Upon activation, B cells express less TGF-b3, which reduces their capacity to expand Treg and which also results in increased Treg death. This may ensure that B cells can function as potent professional antigen presenting cells during infections. However, in the absence of any infection, we find that B-cell-deficient lMT mice have decreased percentages of Treg in the periphery. Our data suggest that resting B cells, which may be presenting self-antigens to T cells, can expand and maintain specific Treg and thus might be involved in the prevention of autoimmunity. Key words: B cells . Regulatory T cells . Tolerance Supporting Information available online IntroductionRegulatory T cells (Treg) are a subset of T cells that can actively suppress innate as well as adaptive immunity and have been implicated in self-tolerance, autoimmunity, cancer, transplantation immunology and a myriad of infectious diseases [1][2][3][4][5][6]. There are numerous different subsets of Treg based on their phenotypic markers, amonge which the naturally occurring Treg (nTreg) population is well studied and characterized. nTreg are a subset of CD4 1 T cells expressing CD25 and the transcription factor Forkhead box protein 3 (Foxp3). Foxp3 has been shown to be the master regulator for the generation of nTreg. Although Foxp3 À/À mice lack CD4 1 CD25 1 T cells, expression of Foxp3 in CD4 1 CD25 -T cells is sufficient for converting them into CD4 1 CD25 1 T cells with suppressive function [7,8].CD4 1 CD25 1 Foxp3 1 Treg arise in the thymus and enter into the periphery where they constitute $5-10% of the CD4 1 T cells. nTreg generation in the thymus is thought to require high-affinity peptide-MHC class II interactions in contrast to low-affinity peptide-MHC class II interactions required for positive selection of conventional CD4 1 T cells [9,10]. There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14]. TGF-b1 or IL-10 have been shown to expand Treg and even convert CD4 1 CD25 À T cells into CD4 1 CD25 1 T cells with suppressive functions [13,[15][16][17][18].Antigen presenting cells (APC) express both MHC class II as well as B7 molecules and secrete cytokines that may modulate the differentiation of T cells into either T-effector or T-r...

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

“…GARP is known to bind to TGF-β1, TGF-β2, and TGF-β3 (45). There is evidence that resting B cells express higher levels of TGF-β3 than activated B cells and are able to expand Treg populations in a TGF-β3-dependent mechanism (83). However, GARP is not expressed by resting B cells, which leads us to believe that GARP primarily regulates the bioavailability of TGF-β1 and TGF-β2 isoforms, rather than TGF-β3, to exert its regulatory roles in B cells.…”

Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion

“…18 However, in our TCR-HAxIg-HA mice, there is evidence of B-cell activation (A.S., unpublished results, 2003), and it has been shown that CD40L-activated human B cells can efficiently induce expansion of Tregs, 46 so it is not clear whether the activation state of the B cell plays a role. Cytokines, such as TGF-␤3, 47 TGF-␤1, 48 and IL-10, produced by follicular B cells 49 have also been reported to be involved in Treg induction by B cells. The precise mechanisms and molecules involved in our system are currently under investigation.…”

Transforming Growth Factor-β3 (TGF-β3) Knock-in Ameliorates Inflammation Due to TGF-β1 Deficiency While Promoting Glucose Tolerance

“…In terms of immunoregulation, TGF-␤3 has been shown to be more functionally potent than TGF-␤1 at inducing chemotaxis of human mast cells but is less effective at inhibiting proliferation of these cells (28). In addition, TGF-␤3 has also been reported to be secreted by resting B cells to promote the expansion of CD4 ϩ CD25 ϩ Foxp3 ϩ cells (57). However, combining resting B cells with purified CD4 ϩ CD25 Ϫ T cells did not result in de novo development of Tregs.…”