TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation

Abstract

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 parasites1 and promote the pathological inflammation associated with asthma and allergic diseases2. 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 diseases3-6. 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 inflammation5, 7-12. 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.

GATA-1 regulates the generation and function of basophils

“…2D). A recent study demonstrated that thymic stromal lymphopoietin (TSLP) and IL-3 independently promote basophil hematopoiesis (35). We found that the surface expression of Fig.…”

Immunity to gastrointestinal nematode infections

“…29 The data on TSLP during parasite infections are sparse, but unlike IL-25 and IL-33, which are critical for the expulsion of multiple parasites, TSLP appears to be involved only during T. muris but not N. brasiliensis or H. polygyrus infections, 14,32,33 and this is understandable given that TSLP is mainly expressed in the large intestine. 33 TSLP can be directly recognized by dendritic cells 54 as well as basophils, 55 again suggesting that epithelial-derived cytokines can bypass ILC2. Indeed, although the main target of IL-25, IL-33, and TSLP appear to be ILC2, it should be noted that both murine and human memory T cells are strongly activated by IL-25, 41,53 IL-33, 53,56,57 and TSLP, 53,58 without the need for T-cell receptor engagement, 57,59 thus being able to respond to antigen nonspecifically.…”

The underestimated role of basophils in Ph+ chronic myeloid leukaemia

“…This growth factor has been described to induce basophil differentiation and maturation in hematopoietic stem and progenitor cells, but also promotes the viability and activation of mature blood basophils 29, 30, 31, 32. Other basophil growth regulators include granulocyte/macrophage colony‐stimulating factor (GM‐CSF), IL‐5, transforming growth factor‐beta (TGF‐ß) and thymic stromal lymphopoietin (TSLP) 33, 34, 35. In mature basophils, additional factors and molecules, such as complement factors (C3a, C5a) are involved in the regulation of survival, migration, adhesion and activation 36.…”