title: A role for inducible costimulator protein in the CD28- independent mechanism of resistance to Toxoplasma gondii.
abstract: Long-term resistance to Toxoplasma gondii is dependent on the development of parasite-specific T cells that produce IFN-gamma. CD28 is a costimulatory molecule important for optimal activation of T cells, but CD28(-/-) mice are resistant to T. gondii, demonstrating that CD28-independent mechanisms regulate T cell responses during toxoplasmosis. The identification of the B7-related protein 1/inducible costimulator protein (ICOS) pathway and its ability to regulate the production of IFN-gamma suggested that this pathway may be involved in the CD28-independent activation of T cells required for resistance to T. gondii. In support of this hypothesis, infection of wild-type or CD28(-/-) mice with T. gondii resulted in the increased expression of ICOS by activated CD4(+) and CD8(+) T cells. In addition, both costimulatory pathways contributed to the in vitro production of IFN-gamma by parasite-specific T cells and when both pathways were blocked, there was an additive effect that resulted in almost complete inhibition of IFN-gamma production. Although in vivo blockade of the ICOS costimulatory pathway did not result in the early mortality of wild-type mice infected with T. gondii, it did lead to increased susceptibility of CD28(-/-) mice to T. gondi associated with reduced serum levels of IFN-gamma, increased parasite burden, and increased mortality compared with the control group. Together, these results identify a critical role for ICOS in the protective Th1-type response required for resistance to T. gondii and suggest that ICOS and CD28 are parallel costimulatory pathways, either of which is sufficient to mediate resistance to this intracellular pathogen.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Villegas
authors.forename: Linda A
authors.initials: LA
authors.lastname: Lieberman
authors.forename: Nicola
authors.initials: N
authors.lastname: Mason
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Blass
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Zediak
authors.forename: Robert
authors.initials: R
authors.lastname: Peach
authors.forename: Tom
authors.initials: T
authors.lastname: Horan
authors.forename: Steve
authors.initials: S
authors.lastname: Yoshinaga
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; C556694:Icos protein, mouse; D007106:Immune Sera; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma