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

TitleTSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.
Publication TypeJournal Article
Year of Publication2011
AuthorsSiracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, E Wherry J, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D
JournalNature
Volume477
Issue7363
Pagination229-33
Date Published2011 Sep 8
ISSN1476-4687
KeywordsAnimals, Asthma, Basophils, Cytokines, Dermatitis, Atopic, Food Hypersensitivity, Hematopoiesis, Humans, Hypersensitivity, Immediate, Inflammation, Interleukin-3, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Phenotype, Receptors, Cytokine, Receptors, Interleukin-3, Th2 Cells
Abstract

CD4(+) T-helper type 2 (T(H)2) 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 diseases. 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 T(H)2 cytokine-associated inflammatory diseases. 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(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 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(H)2-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 T(H)2 cytokine-mediated inflammation.

DOI10.1038/nature10329
Alternate JournalNature
PubMed ID21841801
PubMed Central IDPMC3263308
Grant ListAI083480 / AI / NIAID NIH HHS / United States
AI61570 / AI / NIAID NIH HHS / United States
AI74878 / AI / NIAID NIH HHS / United States
AI87990 / AI / NIAID NIH HHS / United States
F31 GM082187 / GM / NIGMS NIH HHS / United States
F32 AI085828 / AI / NIAID NIH HHS / United States
R01 AI061570 / AI / NIAID NIH HHS / United States
R01 AI061570-09 / AI / NIAID NIH HHS / United States
R01 AI074878 / AI / NIAID NIH HHS / United States
R01 AI074878-05 / AI / NIAID NIH HHS / United States
R01 AI095466 / AI / NIAID NIH HHS / United States
R01 AI095466-02 / AI / NIAID NIH HHS / United States
R01 HL107589 / HL / NHLBI NIH HHS / United States
R21 AI083480 / AI / NIAID NIH HHS / United States
R21 AI083480-02 / AI / NIAID NIH HHS / United States
T32 AI060516 / AI / NIAID NIH HHS / United States
U01 AI095608 / AI / NIAID NIH HHS / United States
U01 AI095608-02 / AI / NIAID NIH HHS / United States

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