title: TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.
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.
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Siracusa
authors.forename: Steven A
authors.initials: SA
authors.lastname: Saenz
authors.forename: David A
authors.initials: DA
authors.lastname: Hill
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.forename: Mark B
authors.initials: MB
authors.lastname: Headley
authors.forename: Travis A
authors.initials: TA
authors.lastname: Doering
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Jessup
authors.forename: Lori A
authors.initials: LA
authors.lastname: Siegel
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
authors.forename: Emily C
authors.initials: EC
authors.lastname: Dudek
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Antonella
authors.initials: A
authors.lastname: Cianferoni
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Spergel
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology; D001491:Basophils / Q000166:cytology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000276:immunology; D005512:Food Hypersensitivity / Q000276:immunology; D006410:Hematopoiesis; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018121:Receptors, Cytokine / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: C498762:CRLF2 protein, human; D016207:Cytokines; D007377:Interleukin-3; D018121:Receptors, Cytokine; D016185:Receptors, Interleukin-3; C072185:Csf2rb2 protein, mouse; D000094632:Thymic Stromal Lymphopoietin