title: Th2 cell-intrinsic hypo-responsiveness determines susceptibility to helminth infection.
abstract: 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.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: van der Werf
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Redpath
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D004198:Disease Susceptibility; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005368:Filariasis / Q000276:immunology* / Q000469:parasitology; D005370:Filarioidea / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor