Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals

Abstract

Inhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-β and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-β and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-β and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-β and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus.

CD4+CD25−LAG3+ regulatory T cells in humoral immunity

“…As has already been described, LAG3 + Tregs suppress humoral immune responses in a TGF‐β3‐dependent manner . In addition, we have recently reported that TGF‐β3 regulates humoral immunity in combination with IL‐10 through modulating metabolic signals . TGF‐β3 and IL‐10 synergistically regulate Toll‐like receptor‐mediated humoral immune responses in B cells by suppressing mammalian target of rapamycin signaling both in vivo and in vitro .…”

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

“…TGF-β concentration is one of the determinants for its pro-inflammatory effects. TGF-β1 shows concentration-dependent bifunctional effects in B cells [94], and we have verified that TGF-β3 also has concentration-dependent bifunctional effects [87,96]. Although a combination of TGF-β1 and IL-21 generates mucosal-homing IgA-secreting plasmablasts [43], a role for TGF-β3 in mucosal immunity has not been demonstrated.…”

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

“…This treatment also increased the efficacy of adoptive cell therapy in a model of T cell lymphoma. Similarly, increasing mitochondrial fusion has been shown to increase oxphos in TGFβ and IL10 treated B cells (87). Another way to circumvent the inhibitory effect of TGFβ on oxphos might be to increase the supply of nutrients which can be metabolized by other pathways or to promote mTORC1 activity which preferentially skews metabolism toward glycolysis (e.g., by increasing the availability of amino acids), which seems to be more resistant to TGFβ's negative effects.…”