Dendritic cell expression of the C-type lectin receptor CD209a: A novel innate parasite-sensing mechanism inducing Th17 cells that drive severe immunopathology in murine schistosome infection.
Following infection with the trematode helminth Schistosoma mansoni, CBA mice develop severe parasite egg-induced hepatic granulomatous inflammation as well as prominent CD4(+) T helper 17 (Th17) cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. By comparison, C57BL/6 mice develop mild hepatic immunopathology, egg stimulation of DCs does not result in IL-1β and IL-23 production, and Th17 cells fail to develop. To investigate the reasons for strain-specific differences in antigen presenting cell (APC) reactivity to eggs, we performed a comparative gene profiling analysis of normal bone marrow-derived DCs (BMDCs) and found that CBA DCs display markedly elevated expression of C-type lectin receptors (CLRs). In particular, expression of CD209a, a murine homologue of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN, CD209), was strikingly higher in CBA than BL/6 DCs. High CD209a surface expression was observed in various CBA splenic and granuloma APC subpopulations; however, only DCs, and not macrophages, B cells or neutrophils, were able to induce Th17 cell differentiation in response to schistosome eggs. Lentiviral gene silencing in CBA DCs, and over-expression in BL/6 DCs, demonstrated CD209a to be critical for egg-induced DC IL-1β and IL-23 production necessary for Th17 cell differentiation and expansion. These findings reveal a novel innate parasite-sensing mechanism promoting CD4(+) Th17 cells that mediate severe immunopathology in schistosomiasis.
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA.
Holly E
HE
Ponichtera
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, USA. Electronic address: miguel.stadecker@tufts.edu.
Miguel J
MJ
Stadecker
D056704:Adaptive Immunity; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006099:Granuloma / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D053583:Interleukin-1beta; D053759:Interleukin-23; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C587672:IL1B protein, mouse
CD209a; Dendritic cell; Immunopathology; Schistosomiasis; Th17