Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T_H2 cell subpopulation with enhanced function

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• 作者：Alyssa Mitson-Salazar ; BS^a ; Yuzhi Yin ; MD ; PhD^a ; Daniel L. Wansley ; PhD^a ; Michael Young ; RN^b ; Hyejeong Bolan ; RN^a ; Sarah Arceo ; RN^a ; Nancy Ho ; MD^c ; Christopher Koh ; MD^c ; Joshua D. Milner ; MD^a ; Kelly D. Stone ; MD ; PhD^a ; Stephen A. Wank ; MD^c ; Calman Prussin ; MD^a ; ^{calmanp@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atopic dermatitis ; eosinophilic inflammation ; eosinophilic gastrointestinal disease ; IL-5 ; hematopoietic prostaglandin D synthase ; chemoattractant receptor&ndash ; homologous molecule expressed on TH2 cells ; TH2 ; CD4 ; CD161 ; CD294
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：137
• 期：3
• 页码：907-918.e9
• 全文大小：4852 K

文摘

IL-5⁺ pathogenic effector T_H2 (peT_H2) cells are a T_H2 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_H2 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_H2 and conventional T_H2 (cT_H2) 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_H2 cells were obtained by means of esophagogastroduodenoscopy.

Results

peT_H2 cells were identified as chemoattractant receptor–homologous molecule expressed on T_H2 cells–positive (CRTH2⁺), hematopoietic prostaglandin D synthase–positive CD161^hi CD4 T cells. peT_H2 cells expressed significantly greater IL-5 and IL-13 than did hematopoietic prostaglandin D synthase–negative and CD161⁻ cT_H2 cells. peT_H2 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_H2 cells, peT_H2 cells preferentially expressed receptors for thymic stromal lymphopoietin, IL-25, and IL-33 and demonstrated greater responsiveness to these innate pro-T_H2 cytokines. peT_H2 but not cT_H2 cells produced prostaglandin D₂. In patients with EGID and those with AD, peT_H2 cells expressed gut- and skin-homing receptors, respectively. There were significantly greater numbers of peT_H2 cells in gut tissue from patients with EGID versus NA subjects.

Conclusion

peT_H2 cells are the primary functional proinflammatory human T_H2 cell subpopulation underlying allergic eosinophilic inflammation. The unambiguous phenotypic identification of human peT_H2 cells provides a powerful tool to track these cells in future pathogenesis studies and clinical trials.