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IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

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Abstract

Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response.

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References

  1. Hiroi T, Yanagita M, Iijima H, Iwatani K, Yoshida T, Takatsu K et al. Deficiency of IL-5 receptor a-chain selectively influences the development of the common mucosal immune system-independent IgA-producing B-1 cell in mucosa-associated tissues. J Immunol 1999; 162: 821.

    CAS  PubMed  Google Scholar 

  2. Gardby E, Lane P, Lycke NY . Requirements for B7-CD28 costimulation in mucosal IgA responses: paradoxes observed in CTLA4-H gamma 1 transgenic mice. J Immunol 1998; 161: 49.

    CAS  PubMed  Google Scholar 

  3. Fagarasan S, Honjo T . T-Independent immune response: new aspects of B cell biology. Science 2000; 290: 89.

    Article  CAS  PubMed  Google Scholar 

  4. Berland R, Wortis HH . Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 2002; 20: 253.

    Article  CAS  PubMed  Google Scholar 

  5. Montecino-Rodriguez E, Leathers H, Dorshkind K . Identification of a B-1 B cell-specified progenitor. Nat Immunol 2006; 7: 293.

    Article  CAS  PubMed  Google Scholar 

  6. Ehrenstein MR, Notley CA . The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 2010; 10: 778.

    Article  CAS  PubMed  Google Scholar 

  7. Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM . A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000; 288: 2222.

    Article  CAS  PubMed  Google Scholar 

  8. Kroese FG, Butcher EC, Stall AM, Lalor PA, Adams S, Herzenberg LA . Many of the IgA producing plasma cells in murine gut are derived from self replenishing precursors in the peritoneal cavity. Int Immunol 1989; 1: 75.

    Article  CAS  PubMed  Google Scholar 

  9. Kroese FG, Butcher EC, Stall AM, Herzenberg LA . A major peritoneal reservoir of precursors for intestinal IgA plasma cells. Immunol Invest 1989; 18: 47.

    Article  CAS  PubMed  Google Scholar 

  10. Waldmann TA, Dubois S, Tagaya Y . Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 2001; 14: 105.

    CAS  PubMed  Google Scholar 

  11. Dubois S, Mariner J, Waldmann TA, Tagaya Y . IL-15R alpha recycles and presents IL-15 in trans to neighboring cells. Immunity 2002; 17: 537.

    Article  CAS  PubMed  Google Scholar 

  12. Carson WE, Fehniger TA, Haldar S, Eckhert K, Lindemann MJ, Lai CF et al. A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest 1997; 99: 937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Waldmann TA, Tagaya Y . The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 1999; 17: 19.

    Article  CAS  PubMed  Google Scholar 

  14. Budagian V, Bulanova E, Paus R, Bulfone-Paus S . IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 2006; 17: 259.

    Article  CAS  PubMed  Google Scholar 

  15. Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK . Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 1996; 111: 1706.

    Article  CAS  PubMed  Google Scholar 

  16. Hirose K, Suzuki H, Nishimura H, Mitani A, Washizu J, Matsuguchi T et al. Interleukin-15 may be responsible for early activation of intestinal intraepithelial lymphocytes after oral infection with Listeria monocytogenes in rats. Infect Immun 1998; 66: 5677.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ohteki T, Yoshida H, Matsuyama T, Duncan GS, Mak TW, Ohashi PS . The transcription factor interferon regulatory factor 1 (IRF-1) is important during the maturation of natural killer 1.1+ T cell receptor-α/β+ (NK1+ T) cells, natural killer cells, and intestinal intraepithelial T cells. J Exp Med 1998; 187: 967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yamada K, Kimura Y, Nishimura H, Namii Y, Murase M, Yoshikai Y . Characterization of CD4+CD8αα+ and CD4−CD8αα+ intestinal intraepithelial lymphocytes in rats. Int Immunol 1999; 11: 21.

    Article  CAS  PubMed  Google Scholar 

  19. van Heel DA . Interleukin 15: its role in intestinal inflammation. Gut 2006; 55: 444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Armitage RJ, Macduff BM, Eisenman J, Paxton R, Grabstein KH . IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol 1995; 154: 483.

    CAS  PubMed  Google Scholar 

  21. Hiroi T, Yanagita M, Ohta N, Sakaue G, Kiyono H . IL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses. J Immunol 2000; 165: 4329.

    Article  CAS  PubMed  Google Scholar 

  22. Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D et al. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J Immunol 2003; 170: 711.

    Article  CAS  PubMed  Google Scholar 

  23. Pillai S, Netravali IA, Cariappa A, Mattoo H . Siglecs and immune regulation. Annu Rev Immunol 2012; 30: 357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C, Dalloul AH . Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood 2002; 100: 4537.

    Article  CAS  PubMed  Google Scholar 

  25. Whyte CS, Bishop ET, Rückerl D, Gaspar-Pereira S, Barker RN, Allen JE et al. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J Leukoc Biol 2011; 90: 845.

    Article  CAS  PubMed  Google Scholar 

  26. Riella LV, Paterson AM, Sharpe AH, Chandraker A . Role of the PD-1 pathway in the immune response. Am J Transplant 2012; 12: 2575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Park CS, Yoon SO, Armitage RJ, Choi YS . Follicular dendritic cells produce IL-15 that enhances germinal center B cell proliferation in membrane-bound form. J Immunol 2004; 173: 6676.

    Article  CAS  PubMed  Google Scholar 

  28. Demirci G, Li XC . IL-2 and IL-15 exhibit opposing effects on Fas mediated apoptosis. Cell Mol Immunol 2004; 1: 123.

    CAS  PubMed  Google Scholar 

  29. Steel JC, Ramlogan CA, Yu P, Sakai Y, Forni G, Waldmann TA et al. Interleukin-15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of CD4 help. Cancer Res 2010; 70: 1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Di Sabatino A, Calarota SA, Vidali F, MacDonald TT, Corazza GR . Role of IL-15 in immune-mediated and infectious diseases. Cytokine Growth Factor Rev 2011; 22: 19.

    Article  CAS  PubMed  Google Scholar 

  31. Gill N, Paltser G, Ashkar AA . Interleukin-15 expression affects homeostasis and function of B cells through NK cell-derived interferon-γ. Cell Immunol 2009; 258: 59.

    Article  CAS  PubMed  Google Scholar 

  32. Jellusova J, Düber S, Gückel E, Binder CJ, Weiss S, Voll R et al. Siglec-G regulates B1 cell survival and selection. J Immunol 2010; 185: 3277.

    Article  CAS  PubMed  Google Scholar 

  33. Ding C, Liu Y, Wang Y, Park BK, Wang CY, Zheng P et al. Siglecg limits the size of B1a B cell lineage by down-regulating NFkappaB activation. PLoS One 2007; 2: e997.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Davey GM, Starr R, Cornish AL, Burghardt JT, Alexander WS, Carbone FR et al. SOCS-1 regulates IL-15-driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential. J Exp Med 2005; 202: 1099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ilangumaran S, Ramanathan S, La Rose J, Poussier P, Rottapel R . Suppressor of cytokine signaling 1 regulates IL-15 receptor signaling in CD8+CD44high memory T lymphocytes. J Immunol 2003; 171: 2435.

    Article  CAS  PubMed  Google Scholar 

  36. Nishimura H, Nose M, Hiai H, Minato N, Honjo T . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141.

    Article  CAS  PubMed  Google Scholar 

  37. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291: 319.

    Article  CAS  PubMed  Google Scholar 

  38. Nishimura H, Minato N, Nakano T, Honjo T . Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 1998; 10: 1563.

    Article  CAS  PubMed  Google Scholar 

  39. Zhong X, Tumang J, Gao W, Bai C, Rothstein T . PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH11/VH12 and phosphatidylcholine binding. Eur J Immunol 2007; 37: 2405.

    Article  CAS  PubMed  Google Scholar 

  40. Yu P, Steel JC, Zhang M, Morris JC, Waldmann TA . Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model. Clin Cancer Res 2010; 16: 6019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cole LE, Yang Y, Elkins KL, Fernandez ET, Qureshi N, Shlomchik MJ et al. Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge. Proc Natl Acad Sci USA 2009; 106: 4343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rothstein TL, Griffin DO, Holodick NE, Quach TD, Kaku H . Human B-1 cells take the stage. Ann NY Acad Sci 2013; 1285: 97.

    Article  CAS  PubMed  Google Scholar 

  43. Pagliari D, Cianci R, Frosali S, Landolfi R, Cammarota G, Newton EE et al. The role of IL-15 in gastrointestinal diseases: a bridge between innate and adaptive immune response. Cytokine Growth Factor Rev 2013; 24: 455.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Indian Council of Medical Research (intramural project number IM/TB/12-13/6), the Government of India, New Delhi-110 029, India. AKG and DS are recipients of Senior Research Fellowships from the University Grants Commission (F. No. 2-77/98 (SA-I)), New Delhi-110 002. SM is the recipient of a Senior Research Fellowship from the Council of Scientific and Industrial Research (National Eligibility Test Fellowship No. 09/482(0049)/2009-EMR-I), New Delhi-110 012. RB is the recipient of a Research Scientist position of the project BT/PR8480/MED/29/729/2013 from the Department of Biotechnology, New Delhi 110 003, India.

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  1. Dr T Biswas, Division of Immunology, National Institute of Cholera and Enteric Diseases, P-33, CIT Road, Scheme-XM, Kolkata 700 010, West Bengal, India. E-mail: shigellaporin@yahoo.com

Authors and Affiliations

  1. Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata, India

    Amlan Kanti Ghosh, Debolina Sinha, Subhadeep Mukherjee, Ratna Biswas & Tapas Biswas

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

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Kanti Ghosh, A., Sinha, D., Mukherjee, S. et al. IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression. Cell Mol Immunol 13, 229–239 (2016). https://doi.org/10.1038/cmi.2015.08

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