Publication Date:
2011-08-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siracusa, Mark C -- Saenz, Steven A -- Hill, David A -- Kim, Brian S -- Headley, Mark B -- Doering, Travis A -- Wherry, E John -- Jessup, Heidi K -- Siegel, Lori A -- Kambayashi, Taku -- Dudek, Emily C -- Kubo, Masato -- Cianferoni, Antonella -- Spergel, Jonathan M -- Ziegler, Steven F -- Comeau, Michael R -- Artis, David -- AI083480/AI/NIAID NIH HHS/ -- AI61570/AI/NIAID NIH HHS/ -- AI74878/AI/NIAID NIH HHS/ -- AI87990/AI/NIAID NIH HHS/ -- F31 GM082187/GM/NIGMS NIH HHS/ -- F32 AI085828/AI/NIAID NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI061570-09/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI074878-05/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 AI095466-02/AI/NIAID NIH HHS/ -- R01 HL107589/HL/NHLBI NIH HHS/ -- R21 AI083480/AI/NIAID NIH HHS/ -- R21 AI083480-02/AI/NIAID NIH HHS/ -- T32 AI060516/AI/NIAID NIH HHS/ -- U01 AI095608/AI/NIAID NIH HHS/ -- U01 AI095608-02/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 14;477(7363):229-33. doi: 10.1038/nature10329.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21841801" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Asthma/immunology
;
Basophils/*cytology/metabolism
;
Cytokines/genetics/immunology/*metabolism
;
Dermatitis, Atopic/immunology
;
Food Hypersensitivity/immunology
;
*Hematopoiesis
;
Humans
;
Hypersensitivity, Immediate/*immunology
;
Inflammation/*immunology/*metabolism
;
*Interleukin-3/metabolism
;
Mice
;
Mice, Inbred BALB C
;
Mice, Inbred C57BL
;
Phenotype
;
Receptors, Cytokine/metabolism
;
Receptors, Interleukin-3/deficiency/genetics/metabolism
;
Th2 Cells/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
