Hematopoietic prostaglandin D synthase: Linking pathogenic effector CD4+ TH2 cells to proeosinophilic inflammation in patients with gastrointestinal allergic disorders
2016; Elsevier BV; Volume: 137; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2015.11.032
ISSN1097-6825
AutoresTing Wen, Marc E. Rothenberg, Yui‐Hsi Wang,
Tópico(s)Eosinophilic Disorders and Syndromes
ResumoEosinophilic gastrointestinal disorders (EGIDs) are characterized as gastrointestinal disorders associated with overproduction of local TH2 cytokines, including IL-4, IL-5, and IL-13.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-29Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar Although recent studies have identified multiple hematopoietic cell types to be involved in adverse allergic immune responses in the gastrointestinal tract, the primary cellular sources of TH2 cytokines and their interactions in the pathogenesis of EGIDs remain elusive.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-29Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar Mechanistically, IL-4 secretion results in immunoglobulin class-switching to IgE in B cells2Omori S.A. Cato M.H. Anzelon-Mills A. Puri K.D. Shapiro-Shelef M. Calame K. et al.Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.Immunity. 2006; 25: 545-557Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar and induction of alternatively activated macrophages.3Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003; 3: 23-35Crossref PubMed Scopus (4720) Google Scholar Production of IL-5 promotes the development, function, and survival of eosinophils,4Han S.T. Mosher D.F. IL-5 induces suspended eosinophils to undergo unique global reorganization associated with priming.Am J Respir Cell Mol Biol. 2014; 50: 654-664Crossref PubMed Scopus (23) Google Scholar and IL-13 induces dysregulated expression of epithelial cell–derived genes, including eotaxin 3,5Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (703) Google Scholar desmoglein-1,6Sherrill J.D. Kc K. Wu D. Djukic Z. Caldwell J.M. Stucke E.M. et al.Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.Mucosal Immunol. 2014; 7: 718-729Crossref PubMed Scopus (194) Google Scholar and LRRC31,7D'Mello R.J. Caldwell J.M. Azouz N.P. Wen T. Sherrill J.D. Hogan S.P. et al.LRRC31 is induced by IL-13 and regulates kallikrein expression and barrier function in the esophageal epithelium.Mucosal Immunol. 2015; ([Epub ahead of print])PubMed Google Scholar which have been shown to be involved in eosinophil recruitment and esophageal epithelial barrier functions. In addition, epithelial cell–derived TH2-promoting cytokines, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, are likely to be potential mediators involved in the induction of gastrointestinal allergic diseases.8Wang Y.-H. Liu Y.-J. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses.Clin Exp Allergy. 2009; 39: 798-806Crossref PubMed Scopus (122) Google Scholar, 9Cayrol C. Girard J.P. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy.Curr Opin Immunol. 2014; 31: 31-37Crossref PubMed Scopus (457) Google Scholar TSLP is considered one of the key genes linked to susceptibility to eosinophilic esophagitis,10Rothenberg M.E. Spergel J.M. Sherrill J.D. Annaiah K. Martin L.J. Cianferoni A. et al.Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010; 42: 289-291Crossref PubMed Scopus (349) Google Scholar possibly by instructing dendritic cells to induce CD4+ TH2 cells to differentiate11Liu Y.J. Soumelis V. Watanabe N. Ito T. Wang Y.H. Malefyt R.W. et al.TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation.Annu Rev Immunol. 2007; 25: 193-219Crossref PubMed Scopus (530) Google Scholar and maintain the CD4+ TH2 central memory/effector cell pool.12Wang Y.H. Ito T. Wang Y.H. Homey B. Watanabe N. Martin R. et al.Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells.Immunity. 2006; 24: 827-838Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar IL-25 or IL-17E, a distinct member of the IL-17 cytokine family, functions to amplify the type 2 immune response against parasitic infection and allergic inflammation in the airway and gastrointestinal tract8Wang Y.-H. Liu Y.-J. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses.Clin Exp Allergy. 2009; 39: 798-806Crossref PubMed Scopus (122) Google Scholar, 13Barlow J.L. McKenzie A.N. IL-25: a key requirement for the regulation of type-2 immunity.Biofactors. 2009; 35: 178-182Crossref PubMed Scopus (32) Google Scholar by enhancing effector function of antigen-experienced CD4+ TH2 memory/effector cells, particularly their IL-5 production.14Wang Y.H. Angkasekwinai P. Lu N. Voo K.S. Arima K. Hanabuchi S. et al.IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.J Exp Med. 2007; 204: 1837-1847Crossref PubMed Scopus (535) Google Scholar, 15Islam S.A. Chang D.S. Colvin R.A. Byrne M.H. McCully M.L. Moser B. et al.Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells.Nat Immunol. 2011; 12: 167-177Crossref PubMed Scopus (224) Google Scholar During cellular stress and tissue injury, release of the biologically active form of IL-33, a nuclear cytokine of the IL-1 family, can also activate CD4+ TH2 cells to produce TH2 cytokines.9Cayrol C. Girard J.P. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy.Curr Opin Immunol. 2014; 31: 31-37Crossref PubMed Scopus (457) Google Scholar Furthermore, these TH2-promoting innate cytokines also have a key role in initiating allergic reactions at mucosal sites by activating the newly described type 2 innate lymphoid cells (ILC2s) to produce prodigious amounts of IL-5 and IL-13 cytokines.16Spits H. Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function.Annu Rev Immunol. 2012; 30: 647-675Crossref PubMed Scopus (543) Google Scholar Accumulating evidence suggests a collaborative relationship between the antigen-experienced CD4+ TH2 cells and innate ILC2s,17Mirchandani A.S. Besnard A.G. Yip E. Scott C. Bain C.C. Cerovic V. et al.Type 2 innate lymphoid cells drive CD4+ Th2 cell responses.J Immunol. 2014; 192: 2442-2448Crossref PubMed Scopus (245) Google Scholar, 18Liu B. Lee J.B. Chen C.Y. Hershey G.K. Wang Y.H. Collaborative interactions between type 2 innate lymphoid cells and antigen-specific CD4+ Th2 cells exacerbate murine allergic airway diseases with prominent eosinophilia.J Immunol. 2015; 194: 3583-3593Crossref PubMed Scopus (45) Google Scholar, 19Wilhelm C. Hirota K. Stieglitz B. Van Snick J. Tolaini M. Lahl K. et al.An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation.Nat Immunol. 2011; 12: 1071-1077Crossref PubMed Scopus (381) Google Scholar which are potentially involved in the pathogenesis of EGIDs. Thus, a better defined marker to identify human CD4+ TH2 cells and ILC2s in the gastrointestinal tract will be instrumental in advancing our understanding of EGIDs. One of the key surface markers to identify human circulating CD4+ TH2 cells and ILC2s is the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2),20Nagata K. Tanaka K. Ogawa K. Kemmotsu K. Imai T. Yoshie O. et al.Selective expression of a novel surface molecule by human Th2 cells in vivo.J Immunol. 1999; 162: 1278-1286PubMed Google Scholar, 21Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (896) Google Scholar which is also expressed by eosinophils, basophils, and some CD8+ cells.22Cosmi L. Annunziato F. Iwasaki M. Galli G. Manetti R. Maggi E. et al.CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease.Eur J Immunol. 2000; 30: 2972-2979Crossref PubMed Scopus (222) Google Scholar, 23Nagata K. Hirai H. Tanaka K. Ogawa K. Aso T. Sugamura K. et al.CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s).FEBS Lett. 1999; 459: 195-199Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar CRTH2 is a G protein–coupled receptor for prostaglandin D2 (PGD2) that can selectively induce chemotaxis of CD4+ TH2 cells and eosinophils.24Hirai H. Tanaka K. Yoshie O. Ogawa K. Kenmotsu K. Takamori Y. et al.Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2.J Exp Med. 2001; 193: 255-261Crossref PubMed Scopus (964) Google Scholar Previous studies demonstrate that the frequency of CRTH2+CD4+ T cells is increased in the bronchial lavage fluid and blood of patients with asthma, atopic dermatitis, or both.12Wang Y.H. Ito T. Wang Y.H. Homey B. Watanabe N. Martin R. et al.Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells.Immunity. 2006; 24: 827-838Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 20Nagata K. Tanaka K. Ogawa K. Kemmotsu K. Imai T. Yoshie O. et al.Selective expression of a novel surface molecule by human Th2 cells in vivo.J Immunol. 1999; 162: 1278-1286PubMed Google Scholar Notably, treatments with CRTH2 antagonists can ameliorate the characteristics of asthma and eosinophilic esophagitis in murine and/or human studies.25Uller L. Mathiesen J.M. Alenmyr L. Korsgren M. Ulven T. Hogberg T. et al.Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation.Respir Res. 2007; 8: 16Crossref PubMed Scopus (122) Google Scholar, 26Hall I.P. Fowler A.V. Gupta A. Tetzlaff K. Nivens M.C. Sarno M. et al.Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment.Pulm Pharmacol Ther. 2015; 32: 37-44Crossref PubMed Scopus (75) Google Scholar, 27Straumann A. Hoesli S. Bussmann C. Stuck M. Perkins M. Collins L.P. et al.Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis.Allergy. 2013; 68: 375-385Crossref PubMed Scopus (160) Google Scholar Building on previous findings, in this issue of the Journal, Mitson-Salazar et al28Mitson-Salazar A. Yin Y. Wansley D.L. Young M. Bolan H. Arceo S. et al.Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human TH2 cell subpopulation with enhanced function.J Allergy Clin Immunol. 2016; 137: 907-918Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar report that a subpopulation of CD4+CRTH2+ TH2 cells that express high levels of surface CD161 and intracellular hematopoietic prostaglandin D synthase (hPGDS) are the bona fide CD4+ TH2 cytokine producers, which are termed pathogenic effector TH2 (peTH2) cells. Indeed, intracellular cytokine analysis reveals that these hPGDS-expressing CD4+CRTH2+CD161+ cells are capable of producing higher levels of intracellular IL-5 and IL-13 cytokines after phorbol 12-myristate 13-acetate/ionomycin stimulation than other CD4+CRTH2+ subsets lacking hPGDS. Notably, most of the CD4+CRTH2+ cells within the antrum, duodenum, and esophagus of patients with EGIDs express hPGDS, suggesting that infiltrated CD4+ TH2 cells at sites of eosinophilic inflammation are the potent TH2 cytokine producers, peTH2 cells. It has been well documented that PGD2, which is primarily produced by mast cells, is a potent mediator to promote airway allergic inflammation.29Claar D. Hartert T.V. Peebles Jr., R.S. The role of prostaglandins in allergic lung inflammation and asthma.Expert Rev Respir Med. 2015; 9: 55-72Crossref PubMed Scopus (76) Google Scholar, 30Moore M.L. Peebles Jr., R.S. Update on the role of prostaglandins in allergic lung inflammation: separating friends from foes, harder than you might think.J Allergy Clin Immunol. 2006; 117: 1036-1039Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar A recent study further demonstrates that PGD2 can induce the migration and activation of ILC2s to release IL-5 and IL-13 cytokines.31Xue L. Salimi M. Panse I. Mjosberg J.M. McKenzie A.N. Spits H. et al.Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells.J Allergy Clin Immunol. 2014; 133: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar The new observations in this report point to a plausible notion that the hPGDS-expressing peTH2 cells not only produce IL-5 to activate eosinophils but also have the potential to release PGD2, which recruits and activates CRTH2-expressing ILC2s. Together with previous reports showing that the TSLP gene links to susceptibility to the most common EGID, eosinophilic esophagitis,10Rothenberg M.E. Spergel J.M. Sherrill J.D. Annaiah K. Martin L.J. Cianferoni A. et al.Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010; 42: 289-291Crossref PubMed Scopus (349) Google Scholar and that TSLP-activated dendritic cells induce upregulation of hPGDS expression by CD4+ TH2 memory/effector cells,12Wang Y.H. Ito T. Wang Y.H. Homey B. Watanabe N. Martin R. et al.Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells.Immunity. 2006; 24: 827-838Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar these intriguing findings suggest that the TSLP/CRTH2/hPGDS/PGD2 axis might potentiate a collaborative interaction between peTH2 cells and ILC2s to amplify eosinophilic inflammation, resulting in development of EGIDs (postulated in Fig 1). Detailed characterizations further reveal that peTH2 cells express increased levels of TSLPR, IL17RB, and IL1RL1 transcripts, suggesting that these pathogenic cells might respond directly to the epithelium-derived, TH2-promoting cytokines TSLP, IL-25, and IL-33 at the inflamed mucosal sites of patients with EGID. Indeed, purified peTH2 cells respond to combined IL-25, IL-33, and IL-2 stimulation by expressing increased IL5, IL9, and IL13 transcripts ex vivo. Consistent with previous studies in human subjects,32Lu N. Wang Y.H. Wang Y.H. Arima K. Hanabuchi S. Liu Y.J. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis.J Exp Med. 2009; 206: 2111-2119Crossref PubMed Scopus (62) Google Scholar TSLPR expression is found to be upregulated in peTH2 cells or activated CD4+ T cells. Whether TSLP functions directly to induce increased TH2 cytokine production by peTH2 cells or acts as an IL-7–like cytokine to enhance survival of peTH2 cells remains to be investigated. On the basis of these findings, the authors imply that the environmental cues at the inflamed mucosal sites might endow infiltrated classical CD4+ TH2 cells with the ability to develop into proallergic peTH2 cells with functional resemblance to ILC2s by upregulating the expression of innate cytokine receptors. However, because of the limitation of the intracellular cytokine staining approach in this study, the capacity of purified peTH2 cells to produce IL-5 and IL-13 in response to these TH2-promoting cytokines cannot be evaluated. Thus, the current study cannot conclude whether peTH2 cells are the major IL-5 producers in the gastrointestinal tract, especially because ILC2s are known to be the most potent IL-5 and IL-13 producers.33Neill D.R. Wong S.H. Bellosi A. Flynn R.J. Daly M. Langford T.K. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (1618) Google Scholar Perhaps these antigen-experienced peTH2 cells are responsible for induction of the allergic immune response driven by food ingestion and recruit ILC2s to amplify eosinophilic inflammation at the mucosal sites. Indeed, clinical studies demonstrate that the symptoms of EGIDs can be ameliorated after eliminating instigating foods from the diet,34Henderson C.J. Abonia J.P. King E.C. Putnam P.E. Collins M.H. Franciosi J.P. et al.Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.J Allergy Clin Immunol. 2012; 129: 1570-1578Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar suggesting the importance of antigen-specific peTH2 cells in regulating the pathogenesis of EGIDs. In summary, this study identifies hPDGS as a reliable marker to define peTH2 cells at proeosinophilic inflammatory sites and, potentially, to be a diagnostic tool for EGIDs. These antigen-experienced peTH2 cells are not only potent TH2 cytokine producers but also capable producers of PGD2, which might recruit other CRTH2-expressing cells, such as ILC2s, eosinophils, and basophils, thereby amplifying allergic eosinophilic inflammation. Future characterizations of peTH2 cells by using the hPGDS biomarker and transcriptome and epigenetic approaches will advance our understanding of the roles of peTH2 cells in the pathogenesis of human allergic disorders. We thank Shawna Hottinger for editorial assistance. Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human TH2 cell subpopulation with enhanced functionJournal of Allergy and Clinical ImmunologyVol. 137Issue 3PreviewIL-5+ pathogenic effector TH2 (peTH2) cells are a TH2 cell subpopulation with enhanced proinflammatory function that has largely been characterized in murine models of allergic inflammation. Full-Text PDF
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