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

Mark C. Siracusa, Steven A. Saenz, David A. Hill, Brian S. Kim, Mark B. Headley, Travis A. Doering, E. John Wherry, Heidi K. Jessup, Lori A. Siegel, Taku Kambayashi, Emily C. Dudek, Masato Kubo, Antonella Cianferoni, Jonathan M. Spergel, Steven F. Ziegler, Michael R. Comeau, David Artis

Research output: Contribution to journalArticlepeer-review

372 Scopus citations

Abstract

CD4+ T-helper type 2 (TH2) cells, characterized by their expression of interleukin (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 diseases2. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of TH2 cytokine-associated inflammatory diseases3-6. In support of 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 T H2 cytokine-mediated immunity and inflammation5,7-12. However, the mechanisms through which TSLP induces 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 T H2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and-deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. 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 haematopoiesis and eliciting a population of functionally distinct basophils that promote TH2 cytokine-mediated inflammation.

Original languageEnglish
Pages (from-to)229-233
Number of pages5
JournalNature
Volume477
Issue number7363
DOIs
StatePublished - Sep 8 2011

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