title: Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo.
abstract: Human filarial parasites cause chronic infection associated with long-term down-regulation of the host's immune response. We show here that CD4+ T cell regulation is the main determinant of parasite survival. In a laboratory model of infection, using Litomosoides sigmodontis in BALB/c mice, parasites establish for >60 days in the thoracic cavity. During infection, CD4+ T cells at this site express increasing levels of CD25, CTLA-4, and glucocorticoid-induced TNF receptor family-related gene (GITR), and by day 60, up to 70% are CTLA-4(+)GITR(high), with a lesser fraction coexpressing CD25. Upon Ag stimulation, CD4(+)CTLA-4(+)GITR(high) cells are hyporesponsive for proliferation and cytokine production. To test the hypothesis that regulatory T cell activity maintains hyporesponsiveness and prolongs infection, we treated mice with Abs to CD25 and GITR. Combined Ab treatment was able to overcome an established infection, resulting in a 73% reduction in parasite numbers (p < 0.01). Parasite killing was accompanied by increased Ag-specific immune responses and markedly reduced levels of CTLA-4 expression. The action of the CD25(+)GITR+ cells was IL-10 independent as in vivo neutralization of IL-10R did not restore the ability of the immune system to kill parasites. These data suggest that regulatory T cells act, in an IL-10-independent manner, to suppress host immunity to filariasis.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Laetitia
authors.initials: L
authors.lastname: LeGoff
authors.forename: Anjanette
authors.initials: A
authors.lastname: Harris
authors.forename: Eva
authors.initials: E
authors.lastname: Malone
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005368:Filariasis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D005370:Filarioidea / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000961:Antilymphocyte Serum; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10