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A B-1a cell subset induces Foxp3− T cells with regulatory activity through an IL-10-independent pathway

Cellular & Molecular Immunology volume 12, pages 354–365 (2015)Cite this article

Abstract

Regulatory T (Treg) cells play a critical role in the maintenance of tolerance. B-1a cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-10. While IL-10 has been correlated with the induction of type 1 Treg (Tr1) cells or Tr1-like cells, whether IL-10-producing B-1a cells are able to induce Treg cells, especially the Tr1 lineage, is poorly understood. We have demonstrated that, similar to the reported B-2 cells, B-1a cells are able to convert naïve CD4+CD25− T cells into a subset of T cells with suppressive function, which we called ‘Treg-of-B1a' cells. Treg-of-B1a cells do not express Foxp3, but upregulate the Treg markers OX40, programmed death 1 (PD-1), inducible costimulator (ICOS) and IL-10R. Moreover, Treg-of-B1a cells do not express Foxp3 and produce high levels of IFN-γ and IL-10, but minimal amounts of IL-4; therefore, they resemble Tr1 cells. However, utilizing IL-10−/− mice, we showed that IL-10 was not involved in the induction of Treg-of-B1a cells. On the contrary, CD86-mediated costimulation was essential for B-1a cells to drive the induction of Treg-of-B1a cells. Finally, we demonstrated that, in contrast to the Treg cells generated by B-2 cells that mediate contact-dependent suppression, Treg-of-B1a cells suppress through secreting soluble factors. While Tr1 cells mediate suppression mainly through IL-10 or TGF-β secretion, Treg-of-B1a cells mediate suppression through an IL-10- and TGF-β-independent pathway. Together, these findings suggest that B-1a cells induce a functionally and phenotypically distinct Treg population that is dissimilar to the reported Foxp3+ Treg or Tr1 cells.

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References

  1. Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787.

    CAS  PubMed  Google Scholar 

  2. Mauri C, Bosma A . Immune regulatory function of B cells. Annu Rev Immunol 2012; 30: 221–241.

    Article  CAS  PubMed  Google Scholar 

  3. Bouaziz JD, Yanaba K, Tedder TF . Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev 2008; 224: 201–214.

    Article  CAS  PubMed  Google Scholar 

  4. Hussain S, Delovitch TL . Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J Immunol 2007; 179: 7225–7232.

    Article  CAS  PubMed  Google Scholar 

  5. Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK . Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002; 16: 219–230.

    Article  CAS  PubMed  Google Scholar 

  6. Mauri C, Gray D, Mushtaq N, Londei M . Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003; 197: 489–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vitale G, Mion F, Pucillo C . Regulatory B cells: evidence, developmental origin and population diversity. Mol Immunol 2010; 48: 1–8.

    Article  CAS  PubMed  Google Scholar 

  8. Tu W, Lau YL, Zheng J, Liu Y, Chan PL, Mao H et al. Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood 2008; 112: 2554–2562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reichardt P, Dornbach B, Rong S, Beissert S, Gueler F, Loser K et al. Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse. Blood 2007; 110: 1519–1529.

    Article  CAS  PubMed  Google Scholar 

  10. Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG . Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 2010; 125: 1114–1124.e8.

    Article  CAS  PubMed  Google Scholar 

  11. Chu KH, Chiang BL . Regulatory T cells induced by mucosal B cells alleviate allergic airway hypersensitivity. Am J Respir Cell Mol Biol 2011; 46: 651–659.

    Article  PubMed  Google Scholar 

  12. Chen X, Jensen PE . Cutting edge: primary B lymphocytes preferentially expand allogeneic FoxP3+CD4 T cells. J Immunol 2007; 179: 2046–2050.

    Article  CAS  PubMed  Google Scholar 

  13. Morlacchi S, Soldani C, Viola A, Sarukhan A . Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion. Blood 2011; 118: 984–991.

    Article  CAS  PubMed  Google Scholar 

  14. DiLillo DJ, Matsushita T, Tedder TF . B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann NY Acad Sci 2010; 1183: 38–57.

    Article  CAS  PubMed  Google Scholar 

  15. Fu CL, Chuang YH, Huang HY, Chiang BL . Induction of IL-10 producing CD4+ T cells with regulatory activities by stimulation with IL-10 gene-modified bone marrow derived dendritic cells. Clin Exp Immunol 2008; 153: 258–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG . Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood. 2005; 105: 1162–1169.

    Article  CAS  PubMed  Google Scholar 

  17. Bacchetta R, Gregori S, Roncarolo MG . CD4+ regulatory T cells: mechanisms of induction and effector function. Autoimmun Rev 2005; 4: 491–496.

    Article  PubMed  Google Scholar 

  18. Ahangarani RR, Janssens W, VanderElst L, Carlier V, VandenDriessche T, Chuah M et al. In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J Immunol 2009; 183: 8232–8243.

    Article  PubMed  Google Scholar 

  19. O'Garra A, Chang R, Go N, Hastings R, Haughton G, Howard M . Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol 1992; 22: 711–717.

    Article  CAS  PubMed  Google Scholar 

  20. Reichardt P, Dornbach B, Gunzer M . The molecular makeup and function of regulatory and effector synapses. Immunol Rev 2007; 218: 165–177.

    Article  CAS  PubMed  Google Scholar 

  21. Fujio K, Okamura T, Yamamoto K . The family of IL-10-secreting CD4+ T cells. Adv Immunol 2010; 105: 99–130.

    Article  CAS  PubMed  Google Scholar 

  22. Croft M, So T, Duan W, Soroosh P . The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 2009; 229: 173–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fife BT, Pauken KE . The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann NY Acad Sci 2011; 1217: 45–59.

    Article  CAS  PubMed  Google Scholar 

  24. Chen X, Subleski JJ, Kopf H, Howard OM, Mannel DN, Oppenheim JJ . Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol 2008; 180: 6467–6471.

    Article  CAS  PubMed  Google Scholar 

  25. Han Y, Guo Q, Zhang M, Chen Z, Cao X . CD69+ CD4+ CD25− T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol 2009; 182: 111–120.

    Article  CAS  PubMed  Google Scholar 

  26. Weiss EM, Schmidt A, Vobis D, Garbi N, Lahl K, Mayer CT et al. Foxp3-mediated suppression of CD95L expression confers resistance to activation-induced cell death in regulatory T cells. J Immunol 2011; 187: 1684–1691.

    Article  CAS  PubMed  Google Scholar 

  27. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322: 271–275.

    CAS  PubMed  Google Scholar 

  28. Ji HB, Liao G, Faubion WA, Abadia-Molina AC, Cozzo C, Laroux FS et al. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol 2004; 172: 5823–5827.

    Article  CAS  PubMed  Google Scholar 

  29. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002; 8: 1024–1032.

    Article  CAS  PubMed  Google Scholar 

  30. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011; 34: 566–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Miyara M, Sakaguchi S . Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007; 13: 108–116.

    Article  CAS  PubMed  Google Scholar 

  32. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002; 195: 603–616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Noh G, Lee JH . Regulatory B cells and allergic diseases. Allergy Asthma Immunol Res 2011; 3: 168–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhong X, Gao W, Degauque N, Bai C, Lu Y, Kenny J et al. Reciprocal generation of Th1/Th17 and Treg cells by B1 and B2 B cells. Eur J Immunol 2007; 37: 2400–2404.

    Article  CAS  PubMed  Google Scholar 

  35. Wu K, Bi Y, Sun K, Wang C . IL-10-producing type 1 regulatory T cells and allergy. Cell Mol Immunol 2007; 4: 269–275.

    PubMed  Google Scholar 

  36. Battaglia M, Gregori S, Bacchetta R, Roncarolo M . Tr1 cells: from discovery to their clinical application. Semin Immunol 2006; 18: 120–127.

    Article  CAS  PubMed  Google Scholar 

  37. Margry B, Wieland WH, van Kooten PJ, van Eden W, Broere F . Peritoneal cavity B-1a cells promote peripheral CD4+ T-cell activation. Eur J Immunol 2013; 43: 2317–2326.

    Article  CAS  PubMed  Google Scholar 

  38. Labadi A, Balogh P . Differential preferences in serosal homing and distribution of peritoneal B-cell subsets revealed by in situ CFSE labeling. Int Immunol 2009; 21: 1047–1056.

    Article  CAS  PubMed  Google Scholar 

  39. Gao J, Ma X, Gu W, Fu M, An J, Xing Y et al. Novel functions of murine B1 cells: active phagocytic and microbicidal abilities. Eur J Immunol 2012; 42: 982–992.

    Article  CAS  PubMed  Google Scholar 

  40. Parra D, Rieger AM, Li J, Zhang YA, Randall LM, Hunter CA et al. Pivotal advance: peritoneal cavity B-1 B cells have phagocytic and microbicidal capacities and present phagocytosed antigen to CD4+ T cells. J Leukoc Biol 2012; 91: 525–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hand TW, dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ, Pepper M et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 2012; 337: 1553–1556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported, in part, by a grant, NHRI-EX102-10253SI, from the National Health Research Institute, Republic of China. Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website. (http://www.nature.com/cmi).

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Authors and Affiliations

  1. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Ling-Hui Hsu, Kun-Po Li, Kuan-Hua Chu & Bor-Luen Chiang

  2. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, China

    Bor-Luen Chiang

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Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website. (http://www.nature.com/cmi).

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Hsu, LH., Li, KP., Chu, KH. et al. A B-1a cell subset induces Foxp3− T cells with regulatory activity through an IL-10-independent pathway. Cell Mol Immunol 12, 354–365 (2015). https://doi.org/10.1038/cmi.2014.56

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