Dendritic cell IL-23 and IL-1 production in response to schistosome eggs induces Th17 cells in a mouse strain prone to severe immunopathology.
Infection with schistosomes results in a CD4 T cell-mediated inflammatory reaction against parasite eggs that varies greatly in magnitude both in humans as well as in mice. In the murine disease, the severe form of immunopathology correlates with high levels of IL-17. We now report that live schistosome eggs stimulate dendritic cells from high pathology-prone CBA mice to produce IL-12p40, IL-6, and TGF-beta, whereas those from low pathology-prone BL/6 mice only make TGF-beta. Moreover, egg-stimulated dendritic cells plus naive CD4 T cells from CBA mice resulted in increased levels of IL-6, IL-23, IL-1beta, as well as IL-17 and the chemokines CXCL1, CXCL2, and CCL2, whereas similarly treated BL/6 cell cocultures instead expressed higher IL-4, IL-5, IL-10, and the transcription factor Foxp3. Neutralization of IL-23 and IL-1, but not of IL-6 or IL-21, profoundly inhibited egg-induced IL-17 production in the CBA cocultures. Conversely, stimulation with schistosome eggs in the presence of exogenous IL-23 and IL-1beta induced BL/6 cells to make IL-17. These findings identify IL-23 and IL-1 as critical host factors that drive IL-17 production, and suggest that parasite recognition followed by a genetically determined innate proinflammatory response induces the development of Th17 cells and thus controls the outcome of immunopathology in schistosomiasis.
Shainheit
Mara G
MG
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Smith
Patrick M
PM
Bazzone
Lindsey E
LE
Wang
Andrew C
AC
Rutitzky
Laura I
LI
Stadecker
Miguel J
MJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D005260:Female; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D010063:Ovum / Q000276:immunology* / Q000378:metabolism; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D012720:Severity of Illness Index
D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23