Characterization of cellular and molecular mechanisms underlying TCR-independent IL-15-induced activation of human memory CD8$^+$ T cells

Abstract

Interleukin 15 (IL-15) has been recognized as a key cytokine regulating homeostasis of memory CD8$^+$ T cells. In viral and inflammatory diseases, however, dysregulated expression of IL-15 activates memory CD8$^+$ T cells in a T cell receptor (TCR)-independent manner and promotes innate-like cytotoxicity that is strongly correlated with the disease-specific tissue damage. However, regulatory mechanisms underlying unique phenotypic and functional changes induced by TCR-independent IL-15 stimulation have not been examined in detail. Herein, I examine characteristic features of TCR-independent IL-15-induced activation of human memory CD8$^+$ T cells. I demonstrated upregulated expression of NKG2D/DAP10 as an indicative marker of TCR-independent IL-15-induced activation of human memory CD8$^+$ T cells. In addition, through transcriptome analysis, I established the specific gene signature induced by IL-15 that is unchanged or decreased by TCR stimulation in memory CD8$^+$ T cells. Interestingly, it was found that IL-15-induced activation of memory CD8$^+$ T cells was negatively regulated by calcium-mediated signaling induced by ionomycin treatment. Using various immunosuppressive agents, I demonstrated that while TCR-mediated activation is dependent on calcineurin pathway, IL-15-induced T-cell activation was not suppressed by calcineurin inhibitors. I also found that total CD8$^+$ T cells with age-dependent accumulation of their senescent subsets better respond to IL-15. Moreover, a combination of IL-15 and IL-12/IL-18 synergistically induced TCR-independent cytotoxic functions of memory CD8$^+$ T cells. Furthermore, I showed that although bystander-activated memory CD8$^+$ T cells highly express PD-1, their activation bypasses immunomodulatory signals induced by PD-1 ligands. Data from the current study unveil the fundamental differences in the activation mechanism of memory CD8$^+$ T cells induced by IL-15 and TCR stimulation. Increasing our understanding of underlying mechanisms that are involved in the regulation of IL-15-activated human memory CD8$^+$ T cells will have important clinical implications for a proper management of immunopathologic host injury found in various diseases.