Alyssa Mitson-Salazar1, Yuzhi Yin1, Daniel L Wansley1, Michael Young2, Hyejeong Bolan1, Sarah Arceo1, Nancy Ho3, Christopher Koh3, Joshua D Milner1, Kelly D Stone1, Stephen A Wank3, Calman Prussin4. 1. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 2. Clinical Research Directorate/CMRP, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md. 3. Gastroenterology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md. 4. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: calmanp@gmail.com.
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. CONCLUSION: 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. Published by Elsevier Inc.
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. CONCLUSION: 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. Published by Elsevier Inc.
Authors: David Chiang; Xintong Chen; Stacie M Jones; Robert A Wood; Scott H Sicherer; A Wesley Burks; Donald Y M Leung; Charuta Agashe; Alexander Grishin; Peter Dawson; Wendy F Davidson; Leah Newman; Robert Sebra; Miriam Merad; Hugh A Sampson; Bojan Losic; M Cecilia Berin Journal: J Allergy Clin Immunol Date: 2018-01-31 Impact factor: 10.793
Authors: Kelly M O'Shea; Seema S Aceves; Evan S Dellon; Sandeep K Gupta; Jonathan M Spergel; Glenn T Furuta; Marc E Rothenberg Journal: Gastroenterology Date: 2017-07-27 Impact factor: 22.682
Authors: Felipe A Vieira Braga; Gozde Kar; Marijn Berg; Orestes A Carpaij; Krzysztof Polanski; Lukas M Simon; Sharon Brouwer; Tomás Gomes; Laura Hesse; Jian Jiang; Eirini S Fasouli; Mirjana Efremova; Roser Vento-Tormo; Carlos Talavera-López; Marnix R Jonker; Karen Affleck; Subarna Palit; Paulina M Strzelecka; Helen V Firth; Krishnaa T Mahbubani; Ana Cvejic; Kerstin B Meyer; Kourosh Saeb-Parsy; Marjan Luinge; Corry-Anke Brandsma; Wim Timens; Ilias Angelidis; Maximilian Strunz; Gerard H Koppelman; Antoon J van Oosterhout; Herbert B Schiller; Fabian J Theis; Maarten van den Berge; Martijn C Nawijn; Sarah A Teichmann Journal: Nat Med Date: 2019-06-17 Impact factor: 53.440