IL-15 enhances CCR5-mediated migration of memory CD8+ T cells by upregulating CCR5 expression in the absence of TCR stimulation

During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8+ T cells. [Display omitted] •IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of TCR stimulation•CCR5 is upregulated in IL-15-induced bystander-activated CD8+ T cells•IL-15-treated CD8+ T cells migrate in a CCR5-dependent manner•CCR5 upregulation is associated with liver injury during acute hepatitis A IL-15 induces TCR-independent bystander activation of memory CD8+ T cells. Seo et al. demonstrate that IL-15 upregulates CCR5 expression on memory CD8+ T cells and enhances CCR5-mediated migration. During acute hepatitis A, CCR5 is upregulated in bystander-activated CD8+ T cells and associated with liver injury.