IRAK-2 Regulates IL-1-Mediated Pathogenic Th17 Cell Development in Helminthic Infection

PLoS Pathogens

Miguel J. Stadecker¹  Patrick M. Smith²  Berri Jacque²  Alexander Poltorak²  James R. Conner² 

[1] Department of Pathology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America;Immunology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States of America

关键词: T helper cells;    T cells;    Immunopathology;    Cytokines;    Transcription factors;    Granulomas;    Mouse models;    Schistosoma;   

DOI  :  10.1371/journal.ppat.1002272

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host’s genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1β-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases.

【 授权许可】

CC BY