B Cell Regulation of CD4+CD25+ T Regulatory Cells and IL-10 Via B7 is Essential for Recovery From Experimental Autoimmune Encephalomyelitis

Mann, Monica; Maresz, Katarzyna; Shriver, Leah P.; Tan, Yanping; Dittel, Bonnie N.

doi:10.4049/jimmunol.178.6.3447

Cited by 274 publications

(239 citation statements)

References 48 publications

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“…Others have proposed a regulatory role for B cells, whereby B cells can dampen effector T-cell function by mechanisms such as TGF-b1 or IL-10 secretion, antigen presentation and even direct contact with other immune cells [43]. A recent study shows that B cells regulate CD4 1 CD25 1 Foxp3 1 T cells in a B7-dependent manner, resulting in increased production of IL-10 by the Treg and subsequent recovery from experimental autoimmune encephalomyelitis [44]. Our data might explain how those B cells regulate Treg numbers.…”

Section: Discussionmentioning

confidence: 99%

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

Shah

Qiao

2008

Eur J Immunol

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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...

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Section: Discussionmentioning

confidence: 99%

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

Shah

Qiao

2008

Eur J Immunol

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“…A number of studies suggest that IL-10-producing B cells are important for the generation and/or maintenance of the regulatory T cell (T REG ) pool [46,63-72]. However, a recent study [73] and our previously published data [23] do not support this view.…”

Section: B10 Cell Regulatory Effectsmentioning

confidence: 94%

“…These two studies suggesting that B10 cells are not involved in the generation and maintenance of the T REG pool are both in models of EAE [23,73]. In contrast, only one study suggests that B10 cells are important for the generation and/or maintenance of the T REG pool specifically in EAE [63]. The results of a different study clarify the picture in EAE further by showing that a subset of regulatory B cells control T REG numbers through IL-10-independent mechanisms [34].…”

Section: B10 Cell Regulatory Effectsmentioning

confidence: 99%

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

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“…In this context, our data could suggest that disease resistance may be a result of an immunologic deficit, maybe triggered by a regulatory T cell (Treg cell). Contribution of Treg cells to initiate remission phase in experimental EAE and its deficiency in clinical MS manifestations have been reported (Viglietta et al 2004, Mann et al 2007). Therefore, a very appealing explanation for this striking difference could be the differential sanitation condition used to raise and keep these two colonies.…”

Section: Discussionmentioning

confidence: 99%