T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation.
C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4(+) T-cell-mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg Ag in CFA markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN-gamma and IL-17, which are signature cytokines of distinct Th1- versus Th17-cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T-bet (T-bet(-/-)), which is required for Th1 differentiation and IFN-gamma production. We now report that immunization with soluble egg Ag in CFA caused a significantly greater enhancement of egg-induced hepatic immunopathology in T-bet(-/-) mice compared with WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4(+) T cells, as well as a marked influx of neutrophils. The absence of IFN-gamma in the T-bet(-/-) mice correlated with a marked increase in IL-23p19, IL-17 and TNF-alpha in granulomas and MLN. In contrast, T-bet(-/-) mice had lower levels of IL-4, IL-5 and IL-10 and a reduction in FIZZ1 and FoxP3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and Treg. These findings demonstrate that T-bet-dependent signaling negatively regulates Th17-mediated immunopathology in severe schistosomiasis.
Rutitzky
Laura I
LI
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Smith
Patrick M
PM
Stadecker
Miguel J
MJ
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006099:Granuloma / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000469:parasitology; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000469:parasitology; D000098815:T-bet Transcription Factor
D000947:Antigens, Helminth; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; C413576:Retnla protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma