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

Nature. 2012 Nov 8;491(7423):264-8. doi: 10.1038/nature11501. Epub 2012 Oct 14.

Abstract

B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / genetics
  • Antigens, CD19 / metabolism
  • Autoimmunity / immunology*
  • B-Lymphocytes, Regulatory / cytology
  • B-Lymphocytes, Regulatory / immunology*
  • B-Lymphocytes, Regulatory / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD5 Antigens / metabolism
  • Cell Division
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Receptors, Interleukin-21 / immunology
  • Receptors, Interleukin-21 / metabolism
  • T-Lymphocytes / immunology*

Substances

  • Antigens, CD19
  • CD40 Antigens
  • CD5 Antigens
  • Histocompatibility Antigens Class II
  • Interleukins
  • Receptors, Interleukin-21
  • Interleukin-10
  • interleukin-21