Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.
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.
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Ayumi
A
Yoshizaki
Tomomitsu
T
Miyagaki
David J
DJ
DiLillo
Takashi
T
Matsushita
Mayuka
M
Horikawa
Evgueni I
EI
Kountikov
Rosanne
R
Spolski
Jonathan C
JC
Poe
Warren J
WJ
Leonard
Thomas F
TF
Tedder
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D060151:B-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D018956:CD5 Antigens / Q000378:metabolism; D002455:Cell Division; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D000098546:Interleukin-21
D018941:Antigens, CD19; D019013:CD40 Antigens; D018956:CD5 Antigens; D000949:Histocompatibility Antigens Class II; D007378:Interleukins; D053655:Receptors, Interleukin-21; D016753:Interleukin-10; D000098546:Interleukin-21