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Infection and Immunity, May 2000, p. 2837-2844, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice

Eric N. Villegas,1 Ulrike Wille,1 Linden Craig,1 Peter S. Linsley,2 Donna M. Rennick,3 Robert Peach,4 and Christopher A. Hunter1,*

Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104-60081; Rosetta Inpharmatics, Kirkland, Washington 980342; DNAX Research Institute, Palo Alto, California 94304-11043; and Bristol Myers Squibb Pharmacology Research Institute, Princeton, New Jersey 085434

Received 22 July 1999/Returned for modification 1 September 1999/Accepted 11 January 2000

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.

* Corresponding author. Mailing address: Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Room 226 Rosenthal Building, 3800 Spruce St., Philadelphia, PA 19104-6008. Phone: (215) 573-7772. Fax: (215) 573-7023. E-mail: chunter{at}phl.vet.upenn.edu.

Infection and Immunity, May 2000, p. 2837-2844, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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