title: Blockade of costimulation prevents infection-induced immunopathology in interleukin-10-deficient mice.
abstract: Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-gamma) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-gamma or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-gamma and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-gamma but not IL-12. Further reduction of IFN-gamma production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104-6008, USA.
authors.forename: E N
authors.initials: EN
authors.lastname: Villegas
authors.forename: U
authors.initials: U
authors.lastname: Wille
authors.forename: L
authors.initials: L
authors.lastname: Craig
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: D M
authors.initials: DM
authors.lastname: Rennick
authors.forename: R
authors.initials: R
authors.lastname: Peach
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D005260:Female; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma