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Pathogen Proliferation Governs the Magnitude but Compromises the Function of CD8 T Cells¹

Subash Sad^2,*,, Renu Dudani^*, Komal Gurnani^*, Marsha Russell^*, Henk van Faassen^*, Brett Finlay and Lakshmi Krishnan^*,

^* National Research Council-Institute for Biological Sciences, Ottawa, Ontario; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario; and Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

CD8⁺ T cell memory is critical for protection against many intracellular pathogens. However, it is not clear how pathogen virulence influences the development and function of CD8⁺ T cells. Salmonella typhimurium (ST) is an intracellular bacterium that causes rapid fatality in susceptible mice and chronic infection in resistant strains. We have constructed recombinant mutants of ST, expressing the same immunodominant Ag OVA, but defective in various key virulence genes. We show that the magnitude of CD8⁺ T cell response correlates directly to the intracellular proliferation of ST. Wild-type ST displayed efficient intracellular proliferation and induced increased numbers of OVA-specific CD8⁺ T cells upon infection in mice. In contrast, mutants with defective Salmonella pathogenicity island II genes displayed poor intracellular proliferation and induced reduced numbers of OVA-specific CD8⁺ T cells. However, when functionality of the CD8⁺ T cell response was measured, mutants of ST induced a more functional response compared with the wild-type ST. Infection with wild-type ST, in contrast to mutants defective in pathogenicity island II genes, induced the generation of mainly effector-memory CD8⁺ T cells that expressed little IL-2, failed to mediate efficient cytotoxicity, and proliferated poorly in response to Ag challenge in vivo. Taken together, these results indicate that pathogens that proliferate rapidly and chronically in vivo may evoke functionally inferior memory CD8⁺ T cells which may promote the survival of the pathogen.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Canadian Institutes of Health Research.

² Address correspondence and reprint requests to Dr. Subash Sad, National Research Council of Canada, 1200 Montreal Road, Building M-54, Ottawa, Ontario K1A OR6, Canada. E-mail address: subash.sad{at}nrc.ca

³ Abbreviations used in this paper: LM, Listeria monocytogenes; ST, Salmonella typhimurium; WT, wild type; BHI, brain heart infusion.

This article has been cited by other articles:

				F. C. Stark, S. Sad, and L. Krishnan Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection Cancer Res., May 15, 2009; 69(10): 4327 - 4334. [Abstract] [Full Text] [PDF]