Differential effects of IL-15 on the generation, maintenance and cytotoxic potential of adaptive cellular responses induced by DNA vaccination

Abstract

IL-15 is an important cytokine for the regulation of lymphocyte homeostasis. However, the role of IL-15 in the generation, maintenance and cytotoxic potential of antigen specific T cells is not fully understood. Because the route of antigenic delivery and the vaccine modality could influence the IL-15 requirement for mounting and preserving cytotoxic T cell responses, we have investigated the immunogenicity of DNA-based vaccines in IL-15 KO mice. DNA vaccination with SIV Gag induced antigen-specific CD4(+) and CD8(+) T cells in the absence of IL-15. However, the absolute number of antigen-specific CD8(+) T cells was decreased in IL-15 KO mice compared to WT animals, suggesting that IL-15 is important for the generation of maximal number of antigen-specific CD8(+) T cells. Interestingly, antigen-specific memory CD8 cells could be efficiently boosted 8 months after the final vaccination in both WT and KO strains of mice, suggesting that the maintenance of antigen-specific long-term memory T cells induced by DNA vaccination is comparable in the absence and presence of IL-15. Importantly, boosting by DNA 8-months after vaccination revealed severely reduced granzyme B content in CD8(+) T cells of IL-15 KO mice compared to WT mice. This suggests that the cytotoxic potential of the long-term memory CD8(+) T cells is impaired. These results suggest that IL-15 is not essential for the generation and maintenance of adaptive cellular responses upon DNA vaccination, but it is critical for the preservation of maximal numbers and for the activity of cytotoxic CD8(+) T cells.

Perspectives for immunotherapy: which applications might achieve an HIV functional cure?

“…A dose escalation trial in cART-treated HIV-infected patients showed that IL-7 was well-tolerated and could improve the available TCR repertoire, potentiate cytotoxic T-cell activity and restore CD4 + T-cell homeostasis [49, 50]. On the other hand, supplementation with IL-15 promoted the differentiation of central memory CD4 + T-cells into shorter-lived transitional or effector memory T CD4 + , which are crucial to immune control [51, 52]. Finally, IL-21 improved T-cell cytotoxicity as well as enhancing antibody production and not increasing viral load in chronically untreated SIV-infected macaques.…”

A Possible Role for Idiotype/Anti-idiotype B–T Cell Interactions in Maintaining Immune Memory

“…The published data suggest a role for homeostatic cytokines, such as IL-7 and IL-15, in memory T and B cell survival (9). However, the absence of IL-7 or/and IL-15 only reduces, but not abrogates completely, the generation of the immune memory in different experimental models (9–11). From this, it appears that some memory cells can be generated and maintained in the absence of homeostatic cytokines.…”

“Inflamm‐aging” influences immune cell survival factors in human bone marrow

“…Maintenance of effector/memory CD8 + T cells also requires IL‐7 . The cytokine IL‐15 can contribute to this process, and it is particularly important for the preservation of highly differentiated CD8 + effector T cells . DCs, monocytes (CD14 + ), CD34 + hematopoietic progenitor cells and BM stromal cells have been described to produce IL‐15 .…”