Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions

Yoshizaki, Ayumi; Miyagaki, Tomomitsu; DiLillo, David J.; Matsushita, T.; Horikawa, Mayuka; Kountikov, Evgueni I.; Spolski, Rosanne; Poe, Jonathan C.; Leonard, Warren J.; Tedder, Thomas F.

doi:10.1038/nature11501

Cited by 557 publications

(604 citation statements)

References 37 publications

(66 reference statements)

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“…B10 cell regulation of inflammation and autoimmunity is Ag specific [23,30,36]. The importance of BCR diversity is demonstrated by the fact that B10+ B10 PRO cells are reduced by approximately 90% in transgenic mice with a fixed BCR [37].…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…A recent study revealed the importance of IL-21, major histocompatibility complex class II (MHC-II) and CD40 during cognate interactions with CD4 + T cells in B10 cell development [36]. Ex vivo stimulation of purified spleen CD19 + B cells with IL-21 induced 2.7-fold to 3.2-fold higher B10 cell frequencies, and 4.4-fold to 5.3-fold more IL-10 secretion compared with stimulation with media alone.…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…Both B10 cells and non-B10 cells expressed IL-21R at similar levels, and ex vivo B10, B10pro and CD1d hi CD5 + B cell numbers were similar among IL-21R-deficient (IL-21R --/-- ), MHC-II-deficient (MHC-II --/-- ) and CD40-deficient (CD40 --/-- ) mice. Nevertheless, IL-21R, MHC-II and CD40 appear to be required for B10 cell effector functions, at least in experimental autoimmune encephalomyelitis (EAE) [36]. Regulatory B10 cell function therefore requires IL-21R signaling, as well as CD40 and MHC-II interactions, potentially explaining Ag-specific B10 cell effector function [37].…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…Although cognate interactions with CD4 + T cells are important for B10 cell effector functions [36], T cells do not appear to be required for B10 cell development. B10 cells are present in T cell-deficient nude mice, and their frequencies and numbers are approximately fivefold higher when compared with wildtype mice.…”

Section: Biology Of B10 Cellsmentioning

confidence: 99%

“…In CD4 + T cells, IL-10 suppresses T H1 [50] and enhances T H2 polarization [41,59]. B10 cells suppress IFNγ and TNFα responses in vitro [60] and INFγ responses in vivo [36] by Ag-specific CD4 + T cells. Co-culture of mouse CD1d hi CD5 + B cells with CFSE-labeled naive CD4 + T cells suppresses T H17 cell differentiation [61] and IL-10 is known to suppress T H17 responses [62].…”

Section: B10 Cell Regulatory Effectsmentioning

confidence: 99%

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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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Section: Biology Of B10 Cellsmentioning

confidence: 99%

Section: Biology Of B10 Cellsmentioning

confidence: 99%

Section: Biology Of B10 Cellsmentioning

confidence: 99%

Section: Biology Of B10 Cellsmentioning

confidence: 99%

Section: B10 Cell Regulatory Effectsmentioning

confidence: 99%

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

2013

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The Effect of Glatiramer Acetate Therapy on Functional Properties of B Cells From Patients With Relapsing-Remitting Multiple Sclerosis

et al. 2014

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IMPORTANCEThis study describes what is, to our knowledge, the previously unknown effect of glatiramer acetate therapy on B cells in patients with relapsing-remitting multiple sclerosis (MS).OBJECTIVE To determine whether glatiramer acetate therapy normalizes dysregulated B-cell proliferation and cytokine production in patients with MS. DESIGN, SETTING, AND PARTICIPANTS Twenty-two patients with MS who were receiving glatiramer acetate therapy and 22 treatment-naive patients with MS were recruited at The University of Texas Southwestern Medical Center MS clinic. Cell samples from healthy donors were obtained from HemaCare (Van Nuys, California) or Carter Blood Bank (Dallas, Texas). Treatment-naive patients with MS had not received any disease-modifying therapies for at least 3 months before the study.EXPOSURES Glatiramer acetate therapy for at least 3 months at the time of the study. MAIN OUTCOMES AND MEASURES B-cell phenotype and proliferation and immunoglobulin and cytokine secretion.RESULTS A restoration of interleukin 10 production by peripheral B cells was observed in patients undergoing glatiramer acetate therapy as well as a significant reduction of interleukin 6 production in a subset of patients who received therapy for less than 32 months. Furthermore, proliferation in response to high-dose CD40L was altered and immunoglobulin production was elevated in in vitro-activated B cells obtained from patients who received glatiramer acetate.CONCLUSIONS AND RELEVANCE Glatiramer acetate therapy remodels the composition of the B-cell compartment and influences cytokine secretion and immunoglobulin production. These data suggest that glatiramer acetate therapy affects several aspects of dysregulated B-cell function in MS that may contribute to the therapeutic mechanisms of glatiramer acetate.

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Immunological Tolerance: Mechanisms

Zouali

2014

Encyclopedia of Life Sciences

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Immunological tolerance refers to a reduction or complete inhibition of the ability of an individual to mount a specific immune response upon immunisation. Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion, clonal anergy, receptor editing, receptor down‐modulation and lymphocyte sequestration. The number of antigen presenting cells, the number and activity of regulatory T cells and regulatory B cells, the nature and amount of antigenic peptides generated and the presence of co‐stimulatory signals in a particular tissue are also important. Depending on the site and the level of antigen expression, different states of peripheral B‐cell and T‐cell tolerance can be reached. In certain situations, they could act in an additive manner. In humans, induction of immunological tolerance is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance. Key Concepts: Tolerance induction is easier in animals with an immature immune system or with a mature immune system that has been compromised by irradiation, drugs or thoracic drug drainage. In general, when a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance. The introduction route is a key variable in tolerance induction, particularly in adult animals, presumably by determining the accessibility of the antigen to professional antigen presenting cells. The tolerant state is not absolute and tolerance is rarely complete. With time, it gradually wanes and eventually disappears, but it can be deliberately terminated by several means. Persistence of the tolerogen in the periphery and its accessibility to the immune system are generally required to maintain tolerance, which continuously inactivates newly emerging T and B cells that develop in lymphoid organs. T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, a process known as negative selection. Similarly, self‐reactive B cells are purged from the functional repertoire during the transition from the pre‐B to mature B‐cell stage in the bone marrow. Anergy is a functionally silent state induced in B cells and T cells, allowing them to persist functionally inactivated in tolerant animals. Receptor editing is a form of receptor processing that markedly alters the variable region genes expressed by B cells and, consequently, changes the specificity of the surface immunoglobulin and maintains B‐cell tolerance to self. Two functional lymphocyte subsets, called regulatory T cells and regulatory B cells, have recently been found to contribute to the maintenance of the fine equilibrium required for immune tolerance. In humans, induction of immunological tolerance in the adult is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.

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Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions

Cited by 557 publications

References 37 publications

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

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

The Effect of Glatiramer Acetate Therapy on Functional Properties of B Cells From Patients With Relapsing-Remitting Multiple Sclerosis

Immunological Tolerance: Mechanisms

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