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

• Published in: Nature (London) Vol. 491; no. 7423; pp. 264 - 268
• Main Authors: YOSHIZAKI, Ayumi, MIYAGAKI, Tomomitsu, DILILLO, David J, MATSUSHITA, Takashi, HORIKAWA, Mayuka, KOUNTIKOV, Evgueni I, SPOLSKI, Rosanne, POE, Jonathan C, LEONARD, Warren J, TEDDER, Thomas F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 08.11.2012
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Antigens, CD19 - genetics; Antigens, CD19 - metabolism; Autoimmunity; Autoimmunity - immunology; B cells; B-Lymphocytes, Regulatory - cytology; B-Lymphocytes, Regulatory - immunology; B-Lymphocytes, Regulatory - metabolism; Biological and medical sciences; CD40 Antigens - immunology; CD40 Antigens - metabolism; CD5 Antigens - metabolism; Cell Division; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Fundamental and applied biological sciences. Psychology; Health aspects; Histocompatibility Antigens Class II - immunology; Humans; Immune system; Immunology; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukins; Interleukins - immunology; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Physiological aspects; Proteins; Receptors, Interleukin-21 - immunology; Receptors, Interleukin-21 - metabolism; Rodents; T cell receptors; T cells; T-Lymphocytes - immunology; United States; Autoimmunity; Regulation(control); B-Lymphocyte; T-Lymphocyte
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11501

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.