Regulatory T cells enhance mast cell production of IL6 via a TGFβ dependent innate mechanism (168.20)

Abstract

Abstract Recently, Tregs have been proposed to limit mast cell degranulation upon antigen stimulation. However, mast cells also produce many cytokines that regulate both innate and adaptive immunity. Here we show that Tregs inhibit mast cell (BMMC) degranulation but, surprisingly, promotes IL6 in response to innate (LPS or PGN) and adaptive (IgE) activation. This required cell-cell contact and did not require activation via the TCR. Blockade of OX40/OX40L pathway inhibited the Treg effects on BMMC degranulation but had no effect on IL6 production. Conversely, blockade of surface bound-TGFβ ablated IL6 production, suggesting that Tregs influence mast cell responses via distinct mechanisms. Furthermore, TGFβ was sufficient to promote enhanced IL6 but had no effect on degranulation. In innate immunity, IL6 and Tregs have been suggested to influence neutrophil clearance and resolution of inflammation. In an LPS-driven model of lung injury, Treg depletion elevated lung neutrophilia in response to LPS. Similarly, mast cell deficient mice displayed significantly elevated neutrophilia in the lung that was fully corrected upon reconstitution with wildtype mast cells but not by IL6 deficient mast cells, suggesting a critical role for mast cell derived IL-6 in neutrophil clearance during innate inflammation. Our data suggests that Tregs are important in limiting the severity of the inflammatory response during innate activation and that they may do so by promoting mast cell production of IL-6.