This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wille, U. Articles by Hunter, C. A. Search for Related Content PubMed PubMed Citation Articles by Wille, U. Articles by Hunter, C. A.

 Previous Article  |  Next Article 

Infection and Immunity, December 2002, p. 6940-6947, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6940-6947.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Contribution of Interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 Ligand Pathways to the Development of a Pathological T-Cell Response in IL-10-Deficient Mice

Ulrike Wille,^1, Eric N. Villegas,^1, Linden Craig,^1, Robert Peach,² and Christopher A. Hunter^1*

School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,¹ Bristol Myers Squibb Pharmacology Research Institute, Princeton, New Jersey 08543²

Received 2 July 2002/ Returned for modification 26 August 2002/ Accepted 31 August 2002

The ability of interleukin-10 (IL-10) to suppress accessory cell functions required for optimal T-cell activation makes it an important inhibitor of cell-mediated immunity. Thus, after infection with the protozoan parasite Toxoplasma gondii, IL-10 knockout (KO) mice develop a CD4⁺-T-cell-dependent shock-like reaction with high levels of IL-12 and gamma interferon (IFN-) in serum, leading to death of mice during the acute phase of infection. Previous studies from this laboratory have shown that simultaneous blockade of CD28 and CD40 can prevent this lethal reaction by inhibiting the production of IFN-. However, the blockade of costimulation did not affect systemic levels of IL-12. To better understand the relationship between IL-12 and the CD28 and CD40 pathways in mediating immune hyperactivity, antagonists of these factors were used to determine their effects on the development of a pathological T-cell response in IL-10 KO mice. Blockade of IL-12 or the CD28/B7 interaction alone did not affect survival; however, the combined blockade of both pathways resulted in decreased production of IFN- and the survival of IL-10 KO mice. To assess the role of the two ligands for CD28, B7.1 and B7.2, IL-10 KO mice were treated with IL-12 plus B7.1 or B7.2 or the combination of all three antibodies. These studies revealed that blockade of both B7 molecules is required for decreased production of IFN- and survival of infected IL-10 KO mice, suggesting that B7.1 and B7.2 can contribute to the lethal shock-like reaction in IL-10 KO mice. In contrast, neutralization of IL-12 and blockade of the CD40/CD40 ligand (CD40L) interaction in vivo did not alter the production of IFN- and only resulted in a small delay in time to death of mice. Together, these data suggest that the CD28/B7 interaction has a central role in the development of a pathological T-cell response in IL-10 KO mice, which is distinct from the role of the CD40/CD40L and IL-12 pathways.

Editor: W. A. Petri, Jr.

Present address: Vaccine Research Center, NIH, NIAID, Bethesda, MD 20892.

Present address: Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720.

Present address: College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37901.

This article has been cited by other articles:

• Jankovic, D., Kullberg, M. C., Feng, C. G., Goldszmid, R. S., Collazo, C. M., Wilson, M., Wynn, T. A., Kamanaka, M., Flavell, R. A., Sher, A. (2007). Conventional T-bet+Foxp3- Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204: 273-283 [Abstract] [Full Text]  
• Saeij, J. P. J., Boyle, J. P., Coller, S., Taylor, S., Sibley, L. D., Brooke-Powell, E. T., Ajioka, J. W., Boothroyd, J. C. (2006). Polymorphic Secreted Kinases Are Key Virulence Factors in Toxoplasmosis. Science 314: 1780-1783 [Abstract] [Full Text]  
• Atochina, O., Harn, D. (2005). LNFPIII/LeX-Stimulated Macrophages Activate Natural Killer Cells via CD40-CD40L Interaction. CVI 12: 1041-1049 [Abstract] [Full Text]  
• Norose, K., Mun, H.-S., Aosai, F., Chen, M., Piao, L.-X., Kobayashi, M., Iwakura, Y., Yano, A. (2003). IFN-{gamma}-Regulated Toxoplasma gondii Distribution and Load in the Murine Eye. IOVS 44: 4375-4381 [Abstract] [Full Text]