Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Abstract

Interleukin 10-producing regulatory B-cells (Breg-cells) suppress autoimmune diseases while aberrant elevation of Breg-cells prevents sterilizing immunity, promotes carcinogenesis and cancer metastasis by converting resting CD4+ T-cells to regulatory T-cells (Tregs). It is therefore of interest to discover factors that induce Breg-cells. Here we show that IL-35 induces Breg-cells in-vivo and promotes their conversion to a unique Breg subset that produces IL-35 (IL-35+Breg). Treatment of mice with IL-35 conferred protection from uveitis and mice lacking IL-35 or defective in IL-35-signaling produced less Breg-cells and developed severe uveitis. Ex-vivo generated Breg-cells also suppressed uveitis by inhibiting pathogenic Th17/Th1 while promoting Tregs expansion. We further show that IL-35 induced the conversion of human B-cells into Breg-cells and suppressed uveitis by activating STAT1/STAT3 through IL-35-Receptor comprising IL-12Rβ2/IL-27Rα subunits. Discovery that IL-35 converts human B-cells into Breg-cells, allows ex-vivo production of autologous Breg-cells for immunotherapy and investigating Breg/IL-35+Breg cells roles in autoimmune diseases and cancer.

Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis

“…Thus, T reg therapy might be a rational approach for the treatment of lupus. Our previous study has suggested that there may be a feedback loop between T regs and B regs that depends on IL-35 for amplification of the immunosuppressive response [7]. We here demonstrated that thymic B220 recipients following the adoptive transfer of splenic CD5 + CD1d hi B regs from WT NZB/NZW mice [58].…”

“…It is also known that B cells negatively regulate immune responses via production of inhibitory cytokines, such as IL-10 and TGF-b [3,4]. A variety of B reg subsets has been described, and of these, the IL-10-producing B reg subset is the most widely studied [2,[5][6][7]. Splenic IL-10-producing B regs are predominantly found within the minor CD5 + CD1d hi B cell subpopulation [8,9], and although they are found at a low frequency (1-5%) in naïve mice, IL-10-producing B regs are expanded in cases of autoimmunity and can play a key role in controlling disease [9].…”

“…Following the advent of B cell depletion therapy, B regs have elicited the interest of a broad spectrum of immunologists and clinicians [2]. Although B regs have been found to modulate immune responses in autoimmunity [3,4,7], infection [19,20], and cancer [15,16], their physiologic contribution to overall immune homeostasis and their development and function remain unclear.…”

EBI3 regulates the NK cell response to mouse cytomegalovirus infection

“…Crosstalk between NK cells and dendritic cells (DCs) early during MCMV infection affects the outcome of the T-cell responses. IL-10 secreted by various immune cells, including NK cells, dampens the T-cell response by negatively affecting the maturation of DCs, and in the absence of IL-10 secretion of IFNγ and TNFα by NK cells enhances the maturation of DCs, which boosts the T-cell response (11).The cytokine Epstein-Barr virus-induced 3 (EBI3) was first identified in B cells infected with Epstein-Barr virus (12), but several other cells from the immune system have also been found to express and secrete EBI3, including activated DCs, regulatory T cells, and regulatory B cells (13)(14)(15). EBI3 belongs to the IL-12 family of cytokines that consists of the four heterodimeric cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/EBI3), and IL-35 (p35/EBI3), which signal through unique pairings of the five receptor chains IL-12Rβ1, IL-12Rβ2, IL-23R, gp130, and WSX-1 (16).…”

“…The cytokine Epstein-Barr virus-induced 3 (EBI3) was first identified in B cells infected with Epstein-Barr virus (12), but several other cells from the immune system have also been found to express and secrete EBI3, including activated DCs, regulatory T cells, and regulatory B cells (13)(14)(15). EBI3 belongs to the IL-12 family of cytokines that consists of the four heterodimeric cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/EBI3), and IL-35 (p35/EBI3), which signal through unique pairings of the five receptor chains IL-12Rβ1, IL-12Rβ2, IL-23R, gp130, and WSX-1 (16).…”