title: CD209a expression on dendritic cells is critical for the development of pathogenic Th17 cell responses in murine schistosomiasis.
abstract: In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3-grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1β and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell-mediated severe immunopathology in helminthic disease.
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Holly E
authors.initials: HE
authors.lastname: Ponichtera
authors.forename: Mara G
authors.initials: MG
authors.lastname: Shainheit
authors.forename: Beiyun C
authors.initials: BC
authors.lastname: Liu
authors.forename: Raktima
authors.initials: R
authors.lastname: Raychowdhury
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Larkin
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Russo
authors.forename: D Brenda
authors.initials: DB
authors.lastname: Salantes
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.forename: Tae J
authors.initials: TJ
authors.lastname: Yun
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bunnell
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Miguel J
authors.initials: MJ
authors.lastname: Stadecker
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D012547:Schistosoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012552:Schistosomiasis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D053583:Interleukin-1beta; D053759:Interleukin-23; D037181:Lectins, C-Type; D048052:Mitogen-Activated Protein Kinase 3; D019908:Proto-Oncogene Proteins c-raf; D016392:Proto-Oncogene Proteins pp60(c-src); D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
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