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.