The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1β

摘要

CBA mice infected with the helminthSchistosomamansonidevelop severe CD4 T cell-mediated hepaticgranulomatous inflammation against parasite eggs associated with a robust Th17 cell response.We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic (Tg) TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by Tg T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 stimulated by syngeneic IL-12p40-deficient DCs. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficientor IL-1R antagonist treated CBA mice developed markedly reduced hepatic immunopathologywith a dampened egg Ag-specific IL-17 response. These results demonstrate the IL-23-IL-1-IL-17 axis to play a central role in the development of severe schistosome egg-induced immunopathology.