Abstract
During microbial infection, bystander CD8+ Tcells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ Tcells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ Tcells and their migration. IL-15 upregulates CCR5 in memory CD8+ Tcells in the absence of Tcell 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+ Tcells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ Tcells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ Tcells 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+ Tcells.
Highlights
During microbial infection, CD8+ T cells specific to the infecting pathogen are activated by T cell receptors (TCRs) that recognize the epitope peptides presented by major histocompatibility complex class I (MHC class I) molecules
IL-15 induces CCR5 upregulation in memory CD8+ T cells without TCR stimulation In the present study, we focused on CCR7ÀCD45RAÀ effector memory T (TEM) and CCR7ÀCD45RA+ effector memory T (TEMRA) cells; we sorted or gated CCR7À memory CD8+ T cells to investigate the effect of IL-15
NLVPMVATV peptide significantly decreased IL-15-induced CCR5 upregulation, similar to antiCD3. These data are reminiscent of our previous results showing that IL-15 increases NKG2D expression on memory CD8+ T cells only in the absence of TCR stimulation (Kim et al, 2018)
Summary
CD8+ T cells specific to the infecting pathogen are activated by T cell receptors (TCRs) that recognize the epitope peptides presented by major histocompatibility complex class I (MHC class I) molecules. Bystander CD8+ T cells that are specific to antigens other than the infecting pathogens can be activated by antigen-independent mechanisms during certain microbial infections (Kim and Shin, 2019; Tough et al, 1996; Whiteside et al, 2018). Memory CD8+ T cells primed by vesicular stomatitis virus infection were found to be activated by subsequent Listeria infection (Chu et al, 2013). Memory CD8+ T cells primed by lymphocytic choriomeningitis virus or Listeria were activated following Leishmania infection (Crosby et al, 2014). In patients with acute HAV infection, preexisting memory CD8+ T cells that are specific to common viruses, but not HAV, are activated by interleukin (IL) that is over-produced in HAV infection (Kim et al, 2018)
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