Regulatory B Cells

Abstract

B cells are best known for their ability to produce antibodies and instigate immune memory necessary for the protection of the host against foreign stimuli. However, certain subsets of B cells are increasingly shown to be capable of negative immune regulation by counteracting inflammation and suppressing the immune response. These cells are aptly termed ‘regulatory B cells’ or ‘Bregs’ and carry out their function by multiple mechanisms that include production of anti‐inflammatory cytokines and cognate interaction with other immune cells. Bregs are able to restore an immune response to homeostatic levels and as such play crucial roles in health conditions requiring suppression of inflammation and/or maintenance of tolerance such as in autoimmunity, graft tolerance, allergy, infection, cancer and pregnancy. Understanding how these potent and dynamic cells can be controlled in various immune situations offers a promising avenue for the development of novel prophylactic and immune therapy treatments.

Key Concepts

  • Regulatory B cells or Bregs are B‐cell subsets capable of downmodulating the immune response.
  • Bregs can suppress the immune response by producing anti‐inflammatory cytokines such as IL‐10 and TGF‐β, or through cell–cell contact with other immune cells.
  • Bregs can limit the severity and progression of autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis by recruiting regulatory T cells and inhibiting proinflammatory cytokine production by helper T cells.
  • Higher Breg frequency in peripheral circulation is correlated with operational tolerance in transplantation patients.
  • Bregs induce and promote allergen tolerance primarily through IL‐10 production.
  • Bregs can inhibit the immune response to viral, bacterial and parasitic infections, thereby allowing pathogen survival and disease progression.
  • Bregs in tumour sites can hinder effector immune cells from attacking and eliminating cancer cells.
  • In pregnancy, Bregs are likely to play an important role in the induction of maternal tolerance necessary for the successful growth of semiallogeneic foetus.

Keywords: regulatory B cells; immune suppression; tolerance; autoimmunity; cancer; infection; allergy; pregnancy; immune therapy

Figure 1. Mechanisms of Breg suppression. Bregs inhibit Th1 and Th17 responses, inducing a Th2‐like bias to the T‐cell response; Bregs also inhibit cytotoxic CD8+ T cells, curtail effector CD4+ T‐cell proliferation, and abrogate the proinflammatory cytokine response, pushing instead the differentiation of CD4+ T cells into Tregs and Tr1s (left panel). Bregs likewise affect other immune cells such as monocytes, dendritic cells and natural killer cells (right panel).
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References

Baba Y, Matsumoto M and Kurosaki T (2015) Signals controlling the development and activity of regulatory B‐lineage cells. International Immunology 27 (10): 487–493.

Bermejo DA, Jackson SW, Gorosito‐Serran M, et al. (2013) Trypanosoma cruzi trans‐sialidase initiates a program independent of the transcription factors ROR gamma t and Ahr that leads to IL‐17 production by activated B cells. Nature Immunology 14 (5): 514–522.

Blair PA, Norena LY, Flores‐Borja F, et al. (2010) CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32 (1): 129–140.

Bodhankar S, Galipeau D, Vandenbark AA and Offner H (2013) PD‐1 Interaction with PD‐L1 but not PD‐L2 on B‐cells mediates protective effects of estrogen against EAE. Journal of Clinical & Cellular Immunology 4 (3): 143.

Carter NA, Rosser EC and Mauri C (2012) Interleukin‐10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen‐induced arthritis. Arthritis Research and Therapy 14 (1): R32.

Das A, Ellis G, Pallant C, et al. (2012) IL‐10‐producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. Journal of Immunology 189 (8): 3925–3935.

Ding Q, Yeung M, Camirand G, et al. (2011) Regulatory B cells are identified by expression of TIM‐1 and can be induced through TIM‐1 ligation to promote tolerance in mice. Journal of Clinical Investigation 121 (9): 3645–3656.

Duddy M, Niino M, Adatia F, et al. (2007) Distinct effector cytokine profiles of memory and naïve human B cell subsets and implications in multiple sclerosis. Journal of Immunology 178 (10): 6092–6099.

El Fassi D, Nielsen CH, Kjeldsen J, et al. (2008) Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves' disease. Gut 57 (5): 714–715.

Flores‐Borja F, Bosma A, Ng D, et al. (2013) CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Science Translational Medicine 5 (173): 173ra123.

Ganti SN, Albershardt TC, Iritani BM and Ruddell A (2015) Regulatory B cells preferentially accumulate in tumor‐draining lymph nodes and promote tumor growth. Scientific Reports 5: 12255.

Gao N, Dresel J, Eckstein V, et al. (2014) Impaired suppressive capacity of activation‐induced regulatory B cells in systemic lupus erythematosus. Arthritis & Rhematology 66 (10): 2849–2861.

Glatigny S, Wagner CA and Bettelli E (2016) Cutting edge: integrin alpha4 is required for regulatory B cell control of experimental autoimmune encephalomyelitis. Journal of Immunology 196 (9): 3542–3546.

Goetz M, Atreya R, Ghalibafian M, et al. (2007) Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflammatory Bowel Diseases 13 (11): 1365–1368.

Jensen F, Muzzio D, Soldati R, et al. (2013) Regulatory B10 cells restore pregnancy tolerance in a mouse model. Biology of Reproduction 89 (4): 90.1–90.7.

Kamekura R, Shigehara K, Miyajima S, et al. (2015) Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma. Clinical Immunology 158 (2): 204–211.

Katz SI, Parker D and Turk JL (1974) B‐cell suppression of delayed hypersensitivity reactions. Nature 251 (5475): 550–551.

Knippenberg S, Peelen E, Smolders J, et al. (2011) Reduction in IL‐10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. Journal of Neuroimmunology 239 (1–2): 80–86.

Lampropoulou V, Hoehlig K, Roch T, et al. (2008) TLR‐activated B cells suppress T cell‐mediated autoimmunity. Journal of Immunology 180 (7): 4763–4773.

Lee CC and Kung JT (2012) Marginal zone B cell is a major source of IL‐10 in Listeria monocytogenes susceptibility. Journal of Immunology 189: 3319–3327.

Lee KM, Stott RT, Zhao G, et al. (2014) TGF‐beta‐producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. European Journal of Immunology 44 (6): 1728–1736.

Lima J, Martins C, Leandro MJ, et al. (2016) Characterization of B cells in healthy pregnant women from late pregnancy to post‐partum: a prospective observational study. BMC Pregnancy and Childbirth 16 (1): 139.

Lindner S, Dahlke K, Sontheimer K, et al. (2013) Interleukin 21‐induced granzyme B‐expressing B cells infiltrate tumors and regulate T cells. Cancer Research 73 (8): 2468–2479.

Liu ZQ, Wu Y, Song JP, et al. (2013a) Tolerogenic CX3CR1+ B cells suppress food allergy‐induced intestinal inflammation in mice. Allergy 68 (10): 1241–1248.

Liu Y, Chen Y, Li Z, et al. (2013b) Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice. European Journal of Immunology 43 (11): 2907–2918.

Liu Y, Cheng L, Wu S, et al. (2016) IL‐10‐producing regulatory B‐cells suppressed effector T‐cells but enhanced regulatory T‐cells in chronic HBV infection. Clinical Science (London) 130 (11): 907–919.

Lundy SK and Fox DA (2009) Reduced Fas ligand‐expressing splenic CD5+ B lymphocytes in severe collagen‐induced arthritis. Arthritis Research and Therapy 11 (4): R128.

Mann MK, Maresz K, Shriver LP, et al. (2007) B cell regulation of CD4+CD25+ T regulatory cells and IL‐10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. Journal of Immunology 178 (6): 3447–3456.

Matsushita T, Horikawa M, Iwata Y and Tedder TF (2010) Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late‐phase immunopathogenesis. Journal of Immunology 185 (4): 2240–2252.

Menon M, Blair PA, Isenberg DA and Mauri C (2016) A regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity 44 (3): 683–697.

Mizoguchi E, Mizoguchi A, Preffer FI and Bhan AK (2000) Regulatory role of mature B cells in a murine model of inflammatory bowel disease. International Immunology 12 (5): 597–605.

Moreau A, Blair PA, Chai JG, et al. (2015) Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival. European Journal of Immunology 45 (3): 843–853.

Muzzio DO, Ziegler KB, Ehrhardt J, et al. (2016) Marginal zone B cells emerge as a critical component of pregnancy well‐being. Reproduction 151 (1): 29–37.

Natarajan P, Singh A, McNamara JT, et al. (2012) Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF‐beta, and co‐localize with CD4+Foxp3+ T cells. Mucosal Immunology 5 (6): 691–701.

Neves P, Lampropoulou V, Calderon‐Gomez E, et al. (2010) Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity 33 (5): 777–790.

Newell KA, Asare A, Sanz I, et al. (2015) Longitudinal studies of a B cell‐derived signature of tolerance in renal transplant recipients. American Journal of Transplantation 15 (11): 2908–2920.

Nova‐Lamperti E, Chana P, Mobillo P, et al. (2017) Increased CD40 ligation and reduced BCR signalling leads to higher IL‐10 production in B cells from tolerant kidney transplant patients. Transplantation 101 (3): 541–547.

Olkhanud PB, Damdinsuren B, Bodogai M, et al. (2011) Tumor‐evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T‐regulatory cells. Cancer Research 71 (10): 3505–3515.

Ray A, Wang L and Dittel BN (2015) IL‐10‐independent regulatory B‐cell subsets and mechanisms of action. International Immunology 27 (10): 531–536.

Rolle L, Memarzadeh Tehran M, Morell‐Garcia A, et al. (2013) Cutting edge: IL‐10‐producing regulatory B cells in early human pregnancy. American Journal of Reproductive Immunology 70 (6): 448–453.

Sarvaria A, Madrigal JA and Saudemont A (2017) B cell regulation in cancer and anti‐tumor immunity. Cellular and molecular immunology 14 (8): 662–674.

Schubert RD, Hu Y, Kumar G, et al. (2015) IFN‐beta treatment requires B cells for efficacy in neuroautoimmunity. Journal of Immunology 194 (5): 2110–2116.

Shen P, Roch T, Lampropoulou V, et al. (2014) IL‐35‐producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507 (7492): 366–370.

Siewe B, Stapleton JT, Martinson J, et al. (2013) Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti‐HIV CD8(+) T cell function in vitro. Journal of Leukocyte Biology 93 (5): 811–818.

van de Veen W, Stanic B, Yaman G, et al. (2013) IgG4 production is confined to human IL‐10‐producing regulatory B cells that suppress antigen‐specific immune responses. Journal of Allergy and Clinical Immunology 131 (4): 1204–1212.

van der Vlugt LE, Mlejnek E, Ozir‐Fazalalikhan A, et al. (2014a) CD24(hi)CD27(+) B cells from patients with allergic asthma have impaired regulatory activity in response to lipopolysaccharide. Clinical and Experimental Allergy 44 (4): 517–528.

van der Vlugt LE, Zinsou JF, Ozir‐Fazalalikhan A, et al. (2014b) Interleukin 10 (IL‐10)‐producing CD1dhi regulatory B cells from Schistosoma haematobium‐infected individuals induce IL‐10‐positive T cells and suppress effector T‐cell cytokines. Journal of Infectious Diseases 210 (8): 1207–1216.

Wang WW, Yuan XL, Chen H, et al. (2015) CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6 (32): 33486–33499.

Weinberg A, Muresan P, Fenton T, et al. (2013) High proportions of regulatory B and T cells are associated with decreased cellular responses to pH1N1 influenza vaccine in HIV‐infected children and youth (IMPAACT P1088). Human Vaccines & Immunotherapeutics 9 (5): 957–968.

Wolf SD, Dittel BN, Hardardottir F and Janeway CA Jr (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell‐deficient mice. Journal of Experimental Medicine 184 (6): 2271–2278.

Zeng H, Zhang R, Jin B and Chen L (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cellular and molecular immunology 12 (5): 566–571.

Zhang Y, Morgan R, Chen C, et al. (2016) Mammary‐tumor‐educated B cells acquire LAP/TGF‐beta and PD‐L1 expression and suppress anti‐tumor immune responses. International Immunology 28 (9): 423–433.

Zhou X, Su YX, Lao XM, et al. (2016) CD19(+)IL‐10(+) regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4(+) T cells to CD4(+)Foxp3(+) regulatory T cells. Oral Oncology 53: 27–35.

Further Reading

Guzman‐Genuino RM and Diener KR (2017) Regulatory B cells in pregnancy: lessons from autoimmunity, graft tolerance, and cancer. Frontiers in Immunology 8: 172.

Mauri C and Menon M (2017) Human regulatory B cells in health and disease: therapeutic potential. Journal of Clinical Investigation 127 (3): 772–779.

Papp G, Boros P, Nakken B, et al. (2017) Regulatory immune cells and functions in autoimmunity and transplantation immunology. Autoimmunity Reviews 16 (5): 435–444.

Rosser EC and Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42 (4): 607–612.

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Guzman‐Genuino, Ruth Marian, and Diener, Kerrilyn R(Jan 2018) Regulatory B Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026235]