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Increased CD8⁺ T Cell Memory to Concurrent Infection at the Expense of Increased Erosion of Pre-existing Memory: The Paradoxical Role of IL-15¹

Laboratory of Cellular Immunology, Institute for Biological Sciences, National Research Council of Canada, Ontario, Canada

The use of cytokines during vaccination, particularly IL-15, is being considered due to the unique ability of IL-15 to enhance the proliferation of memory CD8⁺ T cells. However, as homeostatic mechanisms limit excessive lymphocyte expansion, we addressed the consequences of this enhancement of T cell memory by IL-15. Infection of mice with either recombinant Mycobacterium bovis (BCG) expressing IL-15 (BCG-IL-15) or BCG and purified IL-15 resulted in an increased CD44, IL-2R expression and increased frequency of IFN--secreting CD8⁺ T cells. Surprisingly, the enhancement of memory to concurrent infection by IL-15 exacerbated the attrition of pre-existing memory. Infection of mice with Listeria monocytogenes expressing OVA resulted in potent OVA_257–264-specific CD8⁺ T cell memory, and a challenge of these mice with either BCG-IL-15 or BCG and purified IL-15 resulted in an increased erosion of OVA_257–264-specific CD8⁺ T cell memory, relative to BCG. Enhancement in the erosion of OVA-specific CD8⁺ T cell memory by BCG-IL-15 resulted in a consequently greater impairment in protection against a challenge with OVA-expressing tumor cells. We thus raise important questions regarding vaccinations that are aimed at maximizing T cell memory without considering the impact on pre-existing T cell memory.

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