TY - JOUR
T1 - TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation
AU - Siracusa, Mark C.
AU - Saenz, Steven A.
AU - Hill, David A.
AU - Kim, Brian S.
AU - Headley, Mark B.
AU - Doering, Travis A.
AU - Wherry, E. John
AU - Jessup, Heidi K.
AU - Siegel, Lori A.
AU - Kambayashi, Taku
AU - Dudek, Emily C.
AU - Kubo, Masato
AU - Cianferoni, Antonella
AU - Spergel, Jonathan M.
AU - Ziegler, Steven F.
AU - Comeau, Michael R.
AU - Artis, David
N1 - Funding Information:
Acknowledgements We thank members of the Artis laboratory for critical reading of the manuscript,A. Budelsky,T.Martin, B.-R. Park Yoon, J.Bigler and M.Timour(Amgen) for assistance with experiments and microarrays and the University of Pennsylvania flowcytometrycorefor assistance withsorting.WorkintheArtislaboratoryissupported by the National Institutes of Health (AI61570, AI74878, AI87990 and AI083480 (to D.A.), F32 fellowship AI085828 (to M.C.S.), F31 training grant GM082187 (to S.A.S), T32 training grant AI060516 (to D.A.H.)) and the Burroughs Wellcome Fund (to D.A.).
PY - 2011/9/8
Y1 - 2011/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052582016&partnerID=8YFLogxK
U2 - 10.1038/nature10329
DO - 10.1038/nature10329
M3 - Article
C2 - 21841801
AN - SCOPUS:80052582016
SN - 0028-0836
VL - 477
SP - 229
EP - 233
JO - Nature
JF - Nature
IS - 7363
ER -