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.
Helminth parasites mount chronic infections in over 1 billion people worldwide, of which filarial nematode infections account for 120 million. A major barrier to the development of protective Th2 immunity lies in the dominant down-regulatory immune responses invoked during infection. Although this immune suppression is linked with a range of Th2 cell-extrinsic immune regulators, the fate of CD4+ Th2 cells during chronic infection, and the role of Th2 cell-intrinsic regulation in defining protective immunity to infection is largely unknown. In this study, we use a murine model of filarial nematode infection to show that as infection progresses the Th2 effector cells responsible for killing helminths become functionally hypo-responsive, developing a phenotype similar to adaptive tolerance or exhaustion, and their ability to clear infection becomes impaired. We further demonstrate that we can therapeutically manipulate the intrinsic functional quality of hypo-responsive Th2 cells via the PD-1/PD-L2 co-inhibitory pathway to reawaken them and enhance resistance to infection. Thus, our data provide the first demonstration that Th2 cell-intrinsic hypo-responsiveness plays a key role in determining susceptibility to helminth infection.