Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity

Abstract

Basophils are rare, circulating granulocytes proposed to be involved in T helper (TH) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-alpha in response to immunoglobulin E (IgE) crosslinking. Differentiation of T(H)17 cells requires IL-6 and transforming growth factor (TGF)-beta , but whether basophils play a significant role in T(H)17 induction is unknown. Here we show a role for basophils in T(H)17 cell development by using in vitro T cell differentiation and in vivo T(H)17-mediated inflammation models. Bone marrow derived-basophils (BMBs) and splenic basophils produce significant amounts of IL-6 as well as IL-4 following stimulation with IgE crosslink or cholera toxin (CT). In addition, through IL-6 secretion, BMBs cooperate with dendritic cells to promote T(H)17 cell differentiation. In the TH17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and T(H)17 responses are significantly reduced in the absence of basophils or IL-6. Furthermore, reconstitution with wild-type, but not IL-6-deficient, basophils restored CT-mediated lung inflammation. Lastly, basophil-deficient mice showed reduced phenotypes of T(H)17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of T(H)17 cell differentiation, which is dependent on IL-6 secretion.