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 cytokines, such as IL-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examined the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. We found that IL-15 up-regulates CCR5 in memory CD8+ T cells in the absence of TCR stimulation and enhances CCR5-dependent migration in vitro and in vivo. IL-15-induced CCR5 up-regulation was abrogated by concurrent TCR stimulation, indicating that CCR5 is up-regulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increased proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells. CCR5 up-regulation in bystander-activated CD8+ T cells was associated with severe liver injury in patients with acute hepatitis A. Taken together, the results indicate that CCR5 up-regulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.