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

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. © 2013 van der werf et al.