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A Reduced Antigen Load In Vivo, Rather Than Weak Inflammation, Causes a Substantial Delay in CD8⁺ T Cell Priming against Mycobacterium bovis (Bacillus Calmette-Guérin)¹

Marsha S. Russell^*,, Monica Iskandar^*, Oksana L. Mykytczuk^*, John H. E. Nash^*, Lakshmi Krishnan^*, and Subash Sad^2,*,

^* National Research Council–Institute for Biological Sciences and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Regardless of the dose of Ag, Ag presentation occurs rapidly within the first few days which results in rapid expansion of the CD8⁺ T cell response that peaks at day 7. However, we have previously shown that this rapid priming of CD8⁺ T cells is absent during infection of mice with Mycobacterium bovis (bacillus Calmette-Guérin (BCG)). In this study, we have evaluated the mechanisms responsible for the delayed CD8⁺ T cell priming. Because BCG replicates poorly and survives within phagosomes we considered whether 1) generation of reduced amounts of Ag or 2) weaker activation by pathogen-associated molecular patterns (PAMPs) during BCG infection is responsible for the delay in CD8⁺ T cell priming. Using rOVA-expressing bacteria, our results indicate that infection of mice with BCG-OVA generates greatly reduced levels of OVA, which are 70-fold lower in comparison to the levels generated during infection of mice with Listeria monocytogenes-expressing OVA. Furthermore, increasing the dose of OVA, but not PAMP signaling during BCG-OVA infection resulted in rapid Ag presentation and consequent expansion of the CD8⁺ T cell response, indicating that the generation of reduced Ag levels, not lack of PAMP-associated inflammation, was responsible for delayed priming of CD8⁺ T cells. There was a strong correlation between the relative timing of Ag presentation and the increase in the level of OVA in vivo. Taken together, these results reveal that some slowly replicating pathogens, such as mycobacteria, may facilitate their chronicity by generating reduced Ag levels which causes a substantial delay in the development of acquired immune responses.

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, Institute for Biological Sciences, National Research Council, 1200 Montreal Road, Building M-54, Ottawa, Ontario, Canada K1A 0R6. E-mail address: subash.sad{at}nrc.ca

³ Abbreviations used in this paper: LM, Listeria monocytogenes; BCG, bacillus Calmette-Guérin; BHI, brain heart infusion; PAMP, pathogen-associated molecular pattern.

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