TSLP promotes IL-3-independent basophil hematopoiesis and type 2 inflammation

摘要

CD4⁺ T helper type 2 (Th2) cells characterized by their expression of IL-4, IL-5, IL-9 and IL-13 are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, suggesting that TSLP is a critical regulator of allergic diseases^-. Supporting genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes Th2 cytokine-mediated immunity and inflammation^{, -}. However, the mechanisms through which TSLP promotes Th2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses and that TSLPR-sufficient basophils can restore Th2 cell-dependent immunity in vivo. TSLP acted directly on bone marrow- resident progenitors to selectively promote basophil responses. Critically, TSLP could elicit basophil responses in both IL-3-sufficient and IL-3-deficient environments and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Further, activated human basophils expressed the TSLPR and basophils isolated from eosinophilic esophagitis (EoE) patients were heterogeneous. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil hematopoiesis and eliciting a population of functionally distinct basophils that promote Th2 cytokine-mediated inflammation.