Development and function of regulatory B cells and its role in pregnancy support

Abstract

Traditionally, B cell function is predominantly associated with humoral immunity and positive regulation of the immune response through the production of specific antibodies and optimal activation of CD4+-T cells. However, a unique subclass of B cells has recently been identified, later described as regulatory B cells (B-regulatory, Breg). These cells are capable of suppressing the functions of other immune cells, including dendritic cells (DC) and T-lymphocytes, through the production of anti-inflammatory cytokines, predominantly interleukin(IL)-10, which effectively inhibits the proliferation and production of pro-inflammatory cytokines by T cells and induces the differentiation of regulatory T cells (T-regulatory, Treg cells). Immunosuppressive Bregs that produce IL-10 are involved in maintaining homeostasis in the immune system and self-antigen tolerance. The data obtained confirming the protective role of Bregs in the completion of inflammation, as well as their pathogenic role through the production of autoantibodies. The Breg population includes a unique functionally defined subclass that can currently only be detected by its ability to produce and secrete IL-10 following appropriate ex vivo stimulation. Evidence is now accumulating to support an important role for Bregs in autoimmune and infectious diseases, as well as in the formation of graft tolerance and tumor development. Breg are also involved in the formation of selective immune tolerance during pregnancy, which is necessary to ensure the immuno-privileged microenvironment of the semi-allogeneic fetus. It has been shown that a violation of the number and functional activity of Breg can lead to the development of various immunologically mediated pathologies of pregnancy, such as recurrent implantation failure, recurrent pregnancy loss and premature birth. This review presents the results of studies on the biology and functional role of Breg in the regulation of reproductive processes.

Keywords:регуляторные B-клетки; иммунорегуляция; беременность; иммунная толерантность; интерлейкин-10

Для цитирования: Богданова И.М., Артемьева К.А., Болтовская М.Н. Развитие и функция регуляторных В-клеток и их роль в поддержании беременности. Иммунология. 2021; 42 (4): 415425. DOI: https://doi.org/10.33029/0206-4952-2021-42-4-415-425

Финансирование. Работа выполнена в рамках государственного задания ФГБНУ «Научно-исследовательский институт морфологии человека» ( AAAA-A17-117013050049-3).

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Литература/References

1. Harris D.P., Haynes L., Sayles P.C., Duso D.K., Eaton S.M., Lepak N.M., Johnson L.L., Swain S.L., Lund F.E. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 2000; 1 (6): 475-82. DOI: https://doi.org/10.1038/82717

2. Mauri C. Regulation of immunity and autoimmunity by B cells. Curr. Opin. Immunol. 2010; 22 (6): 761-7. DOI: https://doi.org/10.1015/j.coi. 10.009

3. Лушова А.А., Жеремян Э.А., Астахова Е.А., Спиридонова А.Б., Бязрова М.Г., Филатов А.В. Субпопуляции В-лимфоцитов: функции и молекулярные маркеры. Иммунология. 2019; 40 (6): 63-76. DOI: https://doi.org/10.24411/0206-4952-2019-16009 [Lushova A.A., Zheremyan E.A., Astakhova E.A., Spiridonova A.B., Byazrova M.G., Filatov A.V. B-lymphocyte subsets: functions and molecular markers. Immunologiya. 2019; 40 (6): 63-76. DOI: https://doi.org/10.24411/0206-4952-2019-16009 (in Russian)]

4. Martin F., Chan A.C. Pathogenic roles of B cells in human immunity; insight from the clinic. Immunity. 2004; 20 (5): 517-27. DOI: https://doi.org/10.1016/s1074-76113(04)00112-8

5. Mizoguchi E., Mizoguchi A., Preffer F.I., Bhan A.K. Regulatory role of mature B cells in a murine model of inflammatory bowel disease. Int. Immunol. 2000; 12 (5): 597-605. DOI: https://doi.org/10.1093/intimm/12.5.597

6. Fillatreau S., Swenle C.H., McGeachy M.J., Gray D., Anderton S.M. B cell regulate autoimmunity by provision of IL-10. Nat. Immunol. 2002; 3 (10): 944-50. DOI: https://doi.org/10.1038/ni833

7. Mauri C., Menon M. The expanding family of regulatory B cells. Int. Immunol. 2015; 27 (10): 479-86. DOI: https://doi.org/10.1093/intimm/dxv038

8. Колесникова Н.В., Самойленко Е.С. Роль цитокинов в патогенезе инфекционного эндокардита. Иммунология. 2020; 41 (3): 262-8. DOI: https://doi.org/10.33029/0206-4952-2020-41-3-262-268 [Kolesnikova N.V., Samoylenko E.S. The role of cytokines in the pathogenesis of infective endocarditis. Immunologiya. 2020; 41 (3): 262-8. DOI: https://doi.org/10.33029/0206-4952-2020-41-3-262-268 (in Russian)]

9. Validzadeh A., Sanaei R., Rezaei N., Azizi G., Fekrvand S., Aghamohammadi A., Yazdani R. Potential role of regulatory B cells in immunological diseases. Immunol. Lett. 2019; 215: 48-59. DOI: https://doi.org/10.1016/j.imlet.2019.08.004

10. Mauri C., Bosma A. Immune regulatory function of B cells. Annu. Rev. Immunol. 2012; 30: 221-41. DOI: https://doi.org/10.1146/annurev-immunol-020711-074934

11. Katz S.I., Parker D., Turk J.L. B cell suppression of delayed hypersensitivity reaction. Nature. 1974; 251 (5475): 550-1. DOI: https://doi.org/10.1038/251550a0

12. Neta R., Salvin S.B. Specific suppression of delayed hypersensitivity: the possible presence of a suppressor B cell in regulation of delayed hypersensitivity. J. Immunol. 1974; 113 (6): 1716-25.

13. Vadasz H.T. Kessel A., Toubi E. B-regulatory cells in autoimmunity and immune mediated inflammation. FEBS Lett. 2013; 587 (13): 2074-8. DOI: https://doi.org/10.1016/febslet. 2013.05.023

14. Wolf S.D., Dittel B.N., Hardardottir F., Janeway C.A. Experimental autoimmune encephalitis induction in genetically d-cell deficient mice. J. Exp. Med.1996; 184 (6): 2271-8. DOI: https://doi.org/10.1084/jem.184.6.2271

15. Mizoguchi A., Mizoguchi E., Takedatsu H., Blumderg R.S., Bhan A.K. Chronic intestinal inflammatory condition generates IL-10- producing regulatory B cell subset characterized by Cd1d upregulation. Immunity. 2002; 16 (2): 219-30. DOI: https://doi.org/10.1016/s1074-7613(02)00274-1

16. Mauri C., Gray D., Mishtag N., Londel M. Prevention of arthritis by interleukin 10-producing B cells. J. Exp. Med. 2003; 197 (4): 489-501. DOI: https://doi.org/10.1084/jem20021293

17. Bouaziz J.D., Yanaba K., Tedder T.F. Regulatory B cell as inhibitors of immune responses and inflammation. Immunol. Rev. 2008; 224: 201-14. DOI: https://doi.org/10.1111/j.1600-065X.2008.00661x

18. Busse M., Campe K.J., Nowak D., Schumacher A., Plenagl S., Langwisch S., Tiegs G., Reinhold A., Zenclussen A.C. IL-10 producing B cell rescue mouse fetuses from inflammation-driven fetal death and are able to modulate T cell immune responses. Sci. Rep. 2019; 9 (1): 9335. DOI: https://doi.org/10.1038/s41598-019-45860-2

19. Jensen F., Muzzio D., Soldati R., Fest S., Zenclussen A.C. Regulatory B10 cells restore pregnancy tolerance in a mouse model. Biol. Reprod. 2013; 89 (4): 90. DOI: https://doi.org/10.1095/biolreprod.113.110791

20. Ghaebi M., Nouri M., Ghasemzadeh A., Farzadi L., Jadidi-Niaragh F., Ahmadi M., Yousefi M. Immune regulatory network in successful pregnancy and reproductive failures. Biomed. Pharmacother. 2017; 88: 61-73. DOI: https://doi.org/10.1016/biopha 2017.01.016

21. Sung N., Byeon H.J., Garcia M.D.S., Skariah A., Wu L., Dambaeva S., Beaman K., Gilman-Sachs A., Kwak-Kim J. Deficiency in memory B cell compartment in a patient with infertility and recurrent pregnancy losses. J. Reprod. Immunol. 2016; 118: 70-5. DOI: https://doi.org/10.1016/j.jri.2016.09.003

22. Koushaeian L., Ghorbani F., Ahmadi M., Eghbal-Fard S., Zamani M., Danaii S., Yousefi B., Jadidi-Niaragh F., Hamdi K., Yousefi M. The role of IL-10 producing B cell in repeated implantation failure patients with cellular immune abnormalities. Immunol. Lett. 2019; 214: 16-22. DOI: https://doi.org/10.1016/j.imlet.2019.08.002

23. Abebe E.C., Dejenie T.A., Ayele T.M., Baye N.D., Teshome A.A., Miche Z.T. The role of regulatory B cells in health and disease: a systemic review. J. Inflamm. Res. 2021; 14: 75-84. DOI: https://doi.org/10.2147/JIR.S286426

24. Iwata Y., Matsushita T., Horikawa M., Dilillo D.J., Yanaba K., Venturi G.M., Szabolcs P.M., Bernstein S.H., Magro C.M., Williams A.D., Hall R.P., St Clair W.E., Tedder T.F. Characterization of a rare IL-10-competent B cell subset in human that parallels mouse regulatory B10 cells. Blood. 2011; 117 (2): 530-41. DOI: https://doi.org/10.1182/blood-2010-07-294249

25. Yanaba K., Bouaziz J.D., Haas K.M., Poe J.C., Fujmoto M., Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T-cell-dependent inflammatory responses. Immunity. 2008; 28 (5): 639-50. DOI: https://doi.org/10.1016/j.immu/2008.03.017

26. Rosser E.C., Mauri C. Regulatory B cells: origin, phenotype and function. Immunity. 2015; 42 (4): 607-12. DOI: https://doi.org/10.1016/jimmuni.2015.04.005

27. Mauri C., Menon M. Human regulatory B cells in health and disease: therapeutic potential. J. Clin. Invest. 2017; 127 (3): 772-9. DOI: https://doi.org/10. 1172/jci85113

28. Banko Z., Pozsgay J., Szili D., Toth M., Gati T., Nagy G., Rojkovich B., Sármay G.I Induction and differentiation of IL-10- producing regulatory B cells from healthy blood donors and rheumatoid arthritis patients. J. Immunol. 2017; 198 (4): 1512-20. DOI: https://doi.org/10.4049/jimmunol.1600218

29. Lykken J.M., Candando K.M., Tedder T.F. Regulatory B10 cell development and function. Int. Immunol. 2015; 27 (10): 471-7. DOI: https://doi.org/10. 1093/intimm/dxv046

30. Ding T., Yan F., Cao S., Ren X. Regulatory B cells: new member of immunosuppressive cell club. Hum. Immunol. 2015; 76 (9): 615-21. DOI: https://doi.org/10.1016/humim.2015.09.006

31. Pestka S., Krause C.D., Sarkar D., Walter M.R., Shi Y., Fisher P.B. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 2004; 22: 929-79. DOI: https://doi.org/10.1146//annurev.immunol.22.012703.104622

32. Flores-Borja F., Bosma A., Ng D., Reddy V., Ehrenstein M., Isenborg D.A., Mauri C. CD19+CD24hicd38hi B cells maintain regulatory T cells white limiting TH1 and TT17 differentiation. Sci. Transl. Med. 2013; 5 (173): 173ra23. DOI: https://doi.org/10.1126/scitranslmed.3005407

33. Ray A., Wang I., Dittel B.N. IL-10-independent regulatory B cell subsets and mechanisms of action. Int. Immunol. 2015; 27 (10): 531-6. DOI: https://doi.org/10.1093/intimm/dxv033

34. Tian J., Zekzer D., Hanssen L., Lu Y., Olcott A., Kaufman D.L. Lypopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J. Immunol. 2001; 167 (2): 1081-89. DOI: https://doi.org/10.4049/jimmunol.167.2.1081

35. Parekh V.V., Prasad D.V., Banerjee P.P., Joshi B.N., Kumar A., Mishra G.C. B cell activated lypopolysaccharide, but not by anti-Ig and anti-CD40 antibody induce anergy in CD8+ T cells: role of TGRF-beta 1. J. Immunol. 2003; 170 (12): 5897-911. DOI: https://doi.org/10.4049/jimmunlol.170.12.5897

36. Ran Z., Yue-Bei L., Qui-Ming Z., Huan Y. Regulatory B cells and its role in central nervous system inflammatory demyelinating disease. Front. Immunol. 2020; 11: 1884. DOI: https://doi.org/10.3389/fimmu.2020.01884

37. Xue J.M., Ma F., An Y.F., Suo L.M., Geng X.R., Song Y.N., Mo L.H., Luo X.Q., Zhang X.W., Liu D.B., Zhao C.Q., Yang P.C. Probiotic extracts ameliorate nasal allergy by inducing interleukin-35- producing dendritic cells in mice. Int. Forum Allergy Rhinol. 2019; 9 (11): 1289-96. DOI: https://doi.org/10.1002/alr.22438

38. Shen P., Roch T., Lampropoulou V., O’Connor R.A., Stervbo U., Hilgenberg E., Ries S., Dang V.D., Jaimes Y., Daridon C., Li R., Jouneau L., Boudinot P., Wilantri S., Sakwa I., Miyazaki Y., Leech M.D., McPherson R.C., Wirtz S., Neurath M., Hoehlig K., Meinl E., Grützkau A., Grün J.R., Horn K., Kühl A.A., Dörner T., Bar-Or A., Kaufmann S.H.E., Anderton S.M., Fillatreau S. IL-35-producing B cell are critical regulators of immunity during autoimmune and infectious disease. Nature. 2014; 507 (7492): 366-70. DOI: https://doi.org/10.1038/nature12979/

39. Hilgenberg E., Shen P., Dang V.D., Ries S., Sakwa I., Fillatreau S. Interleukin-10-producing B cells and the regulation of immunity. Curr. Top. Microbiol. Immunol. 2014; 380: 69-92. DOI: https://doi.org/10.1007/978-3-662-43492-5_4

40. Choi J.K., Egwuagu C.E. Interleurin 35 regulatory B cells. J. Mol. Biol. 2021; 433 (1): 166607. DOI: https://doi.org/10.1016/j.jimb.2020.07.019

41. Yoshizaki A., Miyogaki T., DiLillo D.J., Matsushita T., Horikawa M., Kountikov E., Spolski R., Poe J.C., Leonard W.J., Tedder T.F. Regulatory B cells control T cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012; 491 (7423): 264-8. DOI: https://doi.org/10.1038/nature.11501

42. Bermejo D.A., Jackson S.W., Gorosito-Serran M., Acosta-Rodrogues E.V., Amezcua-Vesely M.C., Sather B.D., Singh A.K., Khim S., Mucci J., Liggitt D., Campetella O., Oukka M., Gruppi A., Rawlings D.J. Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells. Nat. Immunol. 2013; 14 (5): 514-22. DOI: https://doi.org/10.1038/ni.2569

43. Lindner S., Dahlke K., Sonthtimer K., Hagn M., Kaltenmeier C., Barth T.F.E., Beyer T., Reister F., Fabricius D., Lotfi R., Lunov O., Nienhaus G.U., Simmet T., Kreienberg R., Möller P., Schrezenmeier H., Jahrsdörfer B. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 2013; 73 (8): 2468-79. DOI: https://doi.org/10.1158/0008-5472.CAN-12-3450

44. Bodhankar S., Galipeau D., Vandenbark A.A., Offner H. PD-1 interaction with PD-L1 but not PD-L2 on B cells mediates protective effects of estrogen against EAE. J. Clin. Cell. Immunol. 2013; 4 (3): 143. DOI: https://doi.org/10.4172/2155-9899.1000143

45. Lopez-Medina M., Carillo-Martin I., Leyva-Rangel J., Alpudche-Aranda C., Ortiz-Navarrete V. Salmonella impairs CD8 T cell response through PD-1:PD-L axis. Immunobiology. 2015; 220 (12): 1369-80. DOI: https://doi.org/10.1016/j.imbio.2015.07.005

46. Lundy S.K., Fox D.A. Reduced Fas ligand-expressing splenic CD5+ B-lymphocytes in severe collagen-induced arthritis. Arthritis Res. Ther. 2009; 11 (4): R128. DOI: https://doi.org/10.1186/ar2795

47. Mizoguchi A., Bhan A.K. A case for regulatory B cells. J. Immunol. 2006; 176 (2): 705-10. DOI: https://doi.org/10.4049/jimmunol.176.2.705

48. Yanaba K., Bouaziz J.-D., Matsushita T., Tsubata T., Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J. Immunol. 2009; 182 (12): 7454-72. DOI: https://doi.org/10.4049/jimmunol.0900270

49. Filatreau S., Manfroi B., Dorner T. Toll-like receptor signaling in B cells during systemic lupus erythematosus. Nat. Rev. Rheumatol. 2021; 17 (2): 98-108. DOI: https://doi.org/10.1038/s41584-020-00544-4

50. Baba Y., Matsumoto M., Kurosaki T. Signals controlling the development and activity of regulatory B-lineage cells. Int. Immunol. 2015; 27 (10): 487-93. DOI: https://doi.org/10.1093/intimm/dxv027

51. Candando K.M., Lykken J.M., Tedder T.F. B10 cell regulation of health and disease. Immunol. Rev. 2014; 259 (1): 259-72. DOI: https://doi.org/10.1111/imr.12176

52. Kimura S., Rickert C., Kojima L., Aburawi M., Tanimine N., Fontan F., Deng K., Tector H., Lee K.M., Yeh H., Markmann J.F. Regulatory B cells require antigen recognition for effective allograft tolerance induction. Am. J. Transplant. 2020; 20 (4): 977-87. DOI: https://doi.org/10.1111/ajt.15739

53. Maseda D., Smith S.H., DiLillo D.J., Bryant J.M., Candando K.M., Weaver C.T., Tedder T.F. Regulatory B10 cells differentiate into antibody-secreting cells after transient IL-10 production in vivo. J. Immunol. 2012; 188 (3): 1036-48. DOI: https://doi.org/10.4049/jimmunol.1102500

54. Arck P.C., Hecher K., Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat. Med. 2013; 19 (5): 548-56. DOI: https://doi.org/10.1038/nm.3160

55. Abu-Raya E., Michalski C., Sadarangani M., Lavoie P.M. Maternal immunological adaptation during normal pregnancy. Front. Immunol. 2020; 11: 575197. DOI: https://doi.org/10.3389/fimmu.2020.575197

56. Guzman-Genuino R.M., Diener K.R. Regulatory B cells in pregnancy: lessons from autoimmunity, graft tolerance, and cancer. Front. Immunol. 2017; 8: 172. DOI: https://doi.org/10.3389/fimmu.2017.00172

57. Dutta S., Sengupta P. Defining pregnancy phases with cytokine shift. J. Pregnancy Reprod. 2017; 1 (4): 1-3. DOI: https://doi.org/10.15761/JPR.1000124

58. Huang N., Chi Y., Qiao J. Role of regulatory T cells in regulating fetal-maternal immune tolerance in healthy pregnancies and reproductive disease. Front. Immunol. 2020; 11: 1023. DOI: https://doi.org/10.3389/fimmu.2020.01023

59. Robertson S.A., Care A.S., Skinner R.J. Interleukin 10 regulates inflammatory cytokine synthesis to protect against lypopolysaccaride-induced abortion and fetal growth restriction in mice. Biol. Reprod. 2007; 76 (5): 738-48. DOI: https://doi.org/10.1095/biolreprod.106.056143

60. Robertson S.A., Skinner R.J., Care A.S. Essential role for IL-10 in resistance to lypopolisaccharide-induced preterm labor in mice. J. Immunol. 2006; 177 (7): 488-96. DOI: https://doi.org/10.4049/jimmunol.177.7.4888

61. Rolle L., Memarzadeh Tehran M., Morell-Garcia A. Cutting edge: IL-10 producing regulatory B cells in early human pregnancy. Am. J. Reprod. Immunol. 2013; 70 (6): 448-53. DOI: https://doi.org/10.1111/aji.1215

62. Fettke F., Schumacher A., Costa S-D., Zenclussen A.C. B cells: the old new players in reproductive immunology. Front. Immunol. 2014; 23 (5): 285. DOI: https://doi.org/10.3389/fimmu.2014.00285

63. Gusman-Genuino R.M., Eldi P., Garcia-Valtanen P., Hayball J.D., Diener K.R. Uterine B cells exhibit regulatory properties during the peri-implantation stage of murine pregnancy. Front. Immunol. 2019; 10: 2899. DOI: https://doi.org/10.3389/fimmu.2o19.02899

64. Guzman-Genuino R.M., Hayball J.D., Diener K.R. Regulatory B cells: dark horse in pregnancy immunotherapy? J. Mol. Biol. 2020; 433 (1): 166596. DOI: https://doi.org/10.1016/j.jmb.2020.07.008

65. Lorek D., Kedzierska A.E., Slawek A., Chelmonska-Soyta A. Expression of Toll-like receptors and costimulatory molecules in splenic B cell in normal and abortion prone murine pregnancy model. Am. J. Reprod. Immunol. 2019; 82 (2): e13148. DOI: https://doi.org/10.1111/aji.13148

66. Dutta S., Sengupta P. Functions of follicular and marginal zone B cells in pregnancy. Asian Pac. J. Reprod. 2018; 7(4): 191-2. DOI: https://doi.org/10.4103/2305-0500.237058

67. Lenert P., Brummel R., Field E.H., Ashman R. TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J. Clin. Immunol. 2005; 25 (1): 29-40. DOI: https://doi.org/10.1007/s10875-005-0355-6

68. Danaii S., Ghorbati F., Ahmadi M., Abbaszadeh H., Koushaeian L., Soltani-Zangbar M.S., Mehdizadeh A., Hojjat-Farsangi M., Kafil H.S., Aghebati-Maleki L., Yousefi M. IL-10-producing B cells play important role in the pathogenesis of recurrent pregnancy loss. Int. Immunopharmacol. 2020; 87: 106806. DOI: https://doi.org/10.1016/j.intimp. 2020.106806

69. Yue C.Y., Zhang B., Ying C.M. Elevated serum level of IL-35 associated with the maintenance of maternal-fetal immune tolerance in normal pregnancy. PLoS One. 2015; 10 (6): e0128219. DOI: https://doi.org/10.1371/journal.pone.0128219

70. Slavek A., Lorek D., Kedzierska A.E., Chelmonska-Soyta A. Regulatory B cells with IL-35 IL-10 expression in a normal and abortion-prone murine pregnancy model. Am. J. Reprod. Immunol. 2020; 83 (3): e13217. DOI: https://doi.org/10.1111/aji.13217

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