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Cross-Reactive Antigen Is Required to Prevent Erosion of Established T Cell Memory and Tumor Immunity: A Heterologous Bacterial Model of Attrition¹

Dean K. Smith^2,*, Renu Dudani^*, Joao A. Pedras-Vasconcelos^*, Yvan Chapdelaine^*, Henk van Faassen^* and Subash Sad^3,*,

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

Induction and maintenance of T cell memory is critical for the control of intracellular pathogens and tumors. Memory T cells seem to require few "maintenance signals," though often such studies are done in the absence of competing immune challenges. Conversely, although attrition of CD8⁺ T cell memory has been characterized in heterologous viral models, this is not the case for bacterial infections. In this study, we demonstrate attrition of T cell responses to the intracellular pathogen Listeria monocytogenes (LM) following an immune challenge with a second intracellular bacterium, Mycobacterium bovis (bacillus Calmette-Guérin, BCG). Mice immunized with either LM or recombinant LM (expressing OVA; LM-OVA), develop a potent T cell memory response. This is reflected by peptide-specific CTL, IFN- production, and frequency of IFN--secreting T cells to native or recombinant LM Ags. However, when the LM-infected mice are subsequently challenged with BCG, there is a marked reduction in the LM-specific T cell responses. These reductions are directly attributable to the effects on CD4⁺ and CD8⁺ T cells and the data are consistent with a loss of LM-specific T cells, not anergy. Attrition of the Ag (OVA)-specific T cell response is prevented when LM-OVA-immunized mice are challenged with a subsequent heterologous pathogen (BCG) expressing OVA, demonstrating memory T cell dependence on Ag. Although the reduction of the LM-specific T cell response did not impair protection against a subsequent LM rechallenge, for the first time, we show that T cell attrition can result in the reduction of Ag-specific antitumor (B16-OVA) immunity previously established with LM-OVA immunization.

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