Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection

PLoS Pathogens

Nienke van der Werf¹  Hideo Yagita²  Stephen A. Redpath³  Miyuki Azuma⁴  Matthew D. Taylor⁵ 

[1] Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada;Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan;Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom

关键词: T helper cells;    T cells;    Helminth infections;    Parasitic diseases;    Nematode infections;    Cytokines;    Macrophages;    Cell-mediated immunity;   

DOI  :  10.1371/journal.ppat.1003215

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environment, and the resultant impact such fate changes may have on host resistance is unknown. We used IL-4gfp reporter mice to demonstrate that during chronic helminth infection with the filarial nematode Litomosoides sigmodontis, CD4+ Th2 cells are conditioned towards an intrinsically hypo-responsive phenotype, characterised by a loss of functional ability to proliferate and produce the cytokines IL-4, IL-5 and IL-2. Th2 cell hypo-responsiveness was a key element determining susceptibility to L. sigmodontis infection, and could be reversed in vivo by blockade of PD-1 resulting in long-term recovery of Th2 cell functional quality and enhanced resistance. Contrasting with T cell dysfunction in Type 1 settings, the control of Th2 cell hypo-responsiveness by PD-1 was mediated through PD-L2, and not PD-L1. Thus, intrinsic changes in Th2 cell quality leading to a functionally hypo-responsive phenotype play a key role in determining susceptibility to filarial infection, and the therapeutic manipulation of Th2 cell-intrinsic quality provides a potential avenue for promoting resistance to helminths.

【 授权许可】

CC BY