title: Differential roles of the co-stimulatory molecules GITR and CTLA-4 in the immune response to Trichinella spiralis.
abstract: We investigated the roles of the regulatory molecules glucocorticoid-induced TNF receptor family-related protein (GITR) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in murine infection with the nematode parasite Trichinella spiralis. Expression of GITR and CTLA-4 was rapidly upregulated on cells in the mesenteric lymph nodes and spleen, with approximately 80% of CD4+ lymphocytes expressing GITR by day 7 post-infection, coinciding with release and dissemination of newborn larvae. As the infection progressed to the chronic muscle phase, expression of GITR returned to normal, whereas CTLA-4 was sustained as late as day 60. Mice treated with anti-GITR antibodies rapidly developed higher titres of parasite-specific IgG1, IgG2a, IgG2b and IgM than controls. This was accompanied by elevated background lymphocyte proliferation, but parasite establishment in the intestine or the muscle was unaffected. In contrast, treatment with anti-CTLA-4 antibody resulted in elevated serum IgE, enhanced production of interleukin-4 and interleukin-10, and lower numbers of parasites recovered from skeletal muscle. These results reveal different temporal and regulatory roles for CTLA-4 and GITR in immune responses to helminth infection.
authors.affiliation: Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Furze
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Culley
authors.forename: Murray E
authors.initials: ME
authors.lastname: Selkirk
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016753:Interleukin-10; D015847:Interleukin-4 / Q000032:analysis; D007422:Intestines / Q000469:parasitology; D008198:Lymph Nodes / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D018482:Muscle, Skeletal / Q000469:parasitology; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D017160:Trichinella spiralis / Q000276:immunology*; D014235:Trichinellosis / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000909:Antibodies, Helminth; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D016753:Interleukin-10; D015847:Interleukin-4; D007073:Immunoglobulin E