Interleukin-35 induces regulatory B cells that suppress autoimmune disease

 Ren-Xi Wang, Cheng-Rong Yu, Ivy M Dambuza, Rashid M Mahdi, Monika B Dolinska, Yuri V Sergeev, Paul T Wingfield, Sung-Hye Kim, and Charles E Egwuagu

Nat Med, 2014, 20(6): 633

Speaker: Chieh-Yu Lin (林倢妤)                                  Time: 13:10~14:00, Apr. 8, 2015

Commentator: Dr. Chrong-Reen Wang (王崇任老師)      Place: Room 601

Abstract:

A subset of regulatory B cells (B_reg cells) that can express IL-10 has been identified in humans and mice. The production of a potent regulatory cytokine, IL-10, is critical for B_reg cells to maintain tolerance to self-antigens, as well as to suppress inflammation, autoimmune disease and antigen-specific immune responses [1]. However, the mechanisms of B_reg cells induction and development remain unclear. In addition to IL-10, B_reg cells may secrete other soluble mediators that contribute to their regulatory function during disease. IL-35 belongs to the IL-12 family, which plays important roles in host immunity. IL-35 suppresses inflammatory responses and limits tissue injury induced by pathogenic T cell subsets [2]. Moreover, IL-35 induces IL-10 production which expands the number of B_reg cells with the ability to suppress autoimmune disease. In this study, the authors examined the role of IL-35, which was first identified as a product of T_reg cells in the context of autoimmune gut inflammation. By generating IL-35 as a fusion protein, this cytokine was shown to induce B_reg cells that secrete both IL-10 and IL-35 (IL-35⁺ B_reg cells). Treating mice with recombinant IL-35 or IL-35⁺ B_reg cells after induction of experimental autoimmune uveitis (EAU), a mouse model of autoimmune eye disease, ameliorated established inflammation by suppressing effector T helper type 17 (T_H17) and T_H1 cell responses and inducing Foxp3⁺ T_reg cells. Furthermore, in order to understand how IL-35 signaling activated the B_reg cell program, the authors examined the requirement for IL-35 cognate receptors. IL-35 receptors can pair as homodimers or heterodimers between different subunits. Whereas IL-35 signals via IL-12Rβ2 and gp130 in T cells, blockade of gp130 had no effect in B cells. Instead, IL-27Rα seemed to couple with IL-12Rβ2 to bind IL-35 in B cells. Moreover, IL-35 signals in B cell transduced and activated through a signal transducer and activator of transcription 1 (STAT1)- and STAT3-dependent manner instead of STAT1-, STAT3-, and STAT4-dependent in T cells. Collectively, these findings show the potential of inhibitory signaling from IL-35 in therapies of autoimmune diseases.

References:

1.         Kalampokis I., et al. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res Ther, 2013, (15): S1.

2.         Collison L.W., et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 2007, (450): 566