title: Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function.
abstract: BACKGROUND
  IL-5(+) pathogenic effector T(H)2 (peT(H)2) cells are a T(H)2 cell subpopulation with enhanced proinflammatory function that has largely been characterized in murine models of allergic inflammation.
  
  
  OBJECTIVE
  We sought to identify phenotype markers for human peT(H)2 cells and characterize their function in patients with allergic eosinophilic inflammatory diseases.
  
  
  METHODS
  Patients with eosinophilic gastrointestinal disease (EGID), patients with atopic dermatitis (AD), and nonatopic healthy control (NA) subjects were enrolled. peT(H)2 and conventional T(H)2 (cT(H)2) cell phenotype, function, and cytokine production were analyzed by using flow cytometry. Confirmatory gene expression was measured by using quantitative RT-PCR. Prostaglandin D2 levels were measured with ELISA. Gut T(H)2 cells were obtained by means of esophagogastroduodenoscopy.
  
  
  RESULTS
  peT(H)2 cells were identified as chemoattractant receptor-homologous molecule expressed on T(H)2 cells-positive (CRTH2(+)), hematopoietic prostaglandin D synthase-positive CD161(hi) CD4 T cells. peT(H)2 cells expressed significantly greater IL-5 and IL-13 than did hematopoietic prostaglandin D synthase-negative and CD161(-) cT(H)2 cells. peT(H)2 cells were highly correlated with blood eosinophilia (r = 0.78-0.98) and were present in 30- to 40-fold greater numbers in subjects with EGID and those with AD versus NA subjects. Relative to cT(H)2 cells, peT(H)2 cells preferentially expressed receptors for thymic stromal lymphopoietin, IL-25, and IL-33 and demonstrated greater responsiveness to these innate pro-TH2 cytokines. peT(H)2 but not cT(H)2 cells produced prostaglandin D2. In patients with EGID and those with AD, peT(H)2 cells expressed gut- and skin-homing receptors, respectively. There were significantly greater numbers of peT(H)2 cells in gut tissue from patients with EGID versus NA subjects.
  
  
  CONCLUSIONS
  peT(H)2 cells are the primary functional proinflammatory human T(H)2 cell subpopulation underlying allergic eosinophilic inflammation. The unambiguous phenotypic identification of human peT(H)2 cells provides a powerful tool to track these cells in future pathogenesis studies and clinical trials.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Mitson-Salazar
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Wansley
authors.affiliation: Clinical Research Directorate/CMRP, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md.
authors.forename: Michael
authors.initials: M
authors.lastname: Young
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Hyejeong
authors.initials: H
authors.lastname: Bolan
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Sarah
authors.initials: S
authors.lastname: Arceo
authors.affiliation: Gastroenterology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ho
authors.affiliation: Gastroenterology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Stone
authors.affiliation: Gastroenterology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wank
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: calmanp@gmail.com.
authors.forename: Calman
authors.initials: C
authors.lastname: Prussin
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007156:Immunologic Memory; D016130:Immunophenotyping; D015848:Interleukin-5 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D054834:Lipocalins / Q000378:metabolism*; D051379:Mice; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D010641:Phenotype; D054388:Receptors, CCR / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D015848:Interleukin-5; D054834:Lipocalins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D054388:Receptors, CCR; D016201:Receptors, Lymphocyte Homing; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: Atopic dermatitis; CD161; CD294; CD4; IL-5; T(H)2; chemoattractant receptor–homologous molecule expressed on T(H)2 cells; eosinophilic gastrointestinal disease; eosinophilic inflammation; hematopoietic prostaglandin D synthase