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)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of TH17 cells requires IL-6 and transforming growth factor (TGF)-β, but whether basophils play a significant role in TH17 induction is unknown. Here we show a role for basophils in TH17 cell development by using in vitro T cell differentiation and in vivo TH17-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 TH17 cell differentiation. In the TH17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and TH17 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 TH17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of TH17 cell differentiation, which is dependent on IL-6 secretion.
Highlights
Basophils, rare circulating granulocytes that account for less than 1% of peripheral blood leukocytes, are characterized by the presence of basophilic granules in the cytoplasm, and express the high affinity receptor for immunoglobulin (Ig) E (FcεRI) and CD49b (DX5)[1,2,3]
In the search for mediators of TH17 cell induction, we focused on basophils since they are recruited to the site of inflammation and once activated, secreting large amounts of IL-6
Because yellow fluorescence protein (YFP) is not expressed in Bone marrow derived-basophils (BMBs) as it is in splenic basophils (SPBs), BMBs cells were identified by their lack of c-kit expression and by expression of CD49b (c-kit−CD49b(DX5)+) (Fig. 1b)
Summary
Rare circulating granulocytes that account for less than 1% of peripheral blood leukocytes, are characterized by the presence of basophilic granules in the cytoplasm, and express the high affinity receptor for immunoglobulin (Ig) E (FcεRI) and CD49b (DX5)[1,2,3] They are usually generated from granulocyte-monocyte progenitors that become basophil lineage-restricted progenitors in the bone marrow (BM)[4]. Many studies have shown that recruitment of basophils to lymph nodes (LNs) is essential and sufficient for TH2 cell differentiation, and basophils may function as antigen presenting cells (APCs), similar to dendritic cells (DCs) and macrophages, since they express MHC class II as well as the co-stimulatory molecules, CD80 and CD8611–15 These studies have been challenged by subsequent findings that both DCs and basophils are required for optimal TH2 responses[16,17,18,19]. We demonstrate that basophils augment TH17 cell differentiation through their cytokine production, and enhance TH17-mediated immune responses in a CT-induced lung inflammation and EAE models
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