Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17.
C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high levels of IFN-gamma. We explored the cause of the severe immunopathology by using IL-12p40(-/-) and IL-12p35(-/-) mice. SEA/CFA-immunized IL-12p40(-/-) mice, incapable of making IL-12 or IL-23, were completely resistant to high pathology, and their SEA-stimulated lymphoid cells failed to secrete significant IFN-gamma or IL-17. In contrast, SEA/CFA-immunized IL-12p35(-/-) mice, able to make IL-23 but not IL-12, developed severe lesions that correlated with high levels of IL-17, low IFN-gamma, and an expansion of activated CD4 T cells with a CD44(high)/CD62L(low) memory phenotype. In vivo administration of neutralizing anti-IL-17 mAb markedly inhibited hepatic granulomatous inflammation. Importantly, CBA mice, a naturally high pathology strain, also displayed elevated IL-17 levels comparable to those seen in the SEA/CFA-immunized BL/6 mice, and their lesions were similarly reduced by in vivo treatment with anti-IL-17. Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis.
Rutitzky
Laura I
LI
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Lopes da Rosa
Jessica R
JR
Stadecker
Miguel J
MJ
D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007114:Immunization; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology*; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17 / Q000032:analysis* / Q000276:immunology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000276:immunology*; D012550:Schistosoma mansoni; D012552:Schistosomiasis / Q000276:immunology / Q000473:pathology*
D000947:Antigens, Helminth; C508841:Il23a protein, mouse; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma