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


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 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, indicating that TSLP is a critical regulator of TH2 cytokine-associated inflammatory diseases3,4,5,6. 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 TH2 cytokine-mediated immunity and inflammation5,7,8,9,10,11,12. 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 TH2-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.

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Figure 1: TSLP promotes peripheral basophilia.
Figure 2: TSLP preferentially expands basophil populations from bone-marrow-resident cells.
Figure 3: TSLP-elicited basophilia is independent of IL-3–IL-3R signalling.
Figure 4: Murine and human basophil populations exhibit heterogeneity.

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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 flow cytometry core for assistance with sorting. Work in the Artis laboratory is supported 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.).

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Authors and Affiliations



M.C.S., S.A.S., D.A.H., B.S.K., M.B.H., H.K.J., L.A.S., M.R.C. and D.A. designed and performed the research. S.F.Z., T.K. and M.K. provided reagents. E.C.D., A.C. and J.M.S. collected and provided human samples. M.C.S., S.A.S., D.A.H., B.S.K., T.A.D., E.J.W and D.A. analysed the data. M.C.S. and D.A. wrote the paper.

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Correspondence to David Artis.

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The authors declare no competing financial interests.

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Siracusa, M., Saenz, S., Hill, D. et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).

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