Basophil-derived IL-6 regulates T_H17 cell differentiation and CD4 T cell immunity

Basophils are rare, circulating granulocytes proposed to be involved in T helper (T_H) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of T_H17 cells requires IL-6 and transforming growth factor (TGF)-β, but whether basophils play a significant role in T_H17 induction is unknown. Here we show a role for basophils in T_H17 cell development by using in vitro T cell differentiation and in vivo T_H17-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_H17 cell differentiation. In the T_H17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and T_H17 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_H17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of T_H17 cell differentiation, which is dependent on IL-6 secretion.