IL-15 regulates memory CD8+ T cell IL-15-glycan synthesis and affects trafficking

Memory and naive CD8(+) T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8(+) ' T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8(+) T cell trafficking are largely unknown. Here, using murine models of infecdon and T cell transfer, we found that memory but not naive CD8(+) T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8(+) T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8(+) T cells. After unrelated infection or inflammatory challenge, memory CD8(+) T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CDS+ T cells exhibited the opposite pattern of epigenetic modifications at the Gcntl locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8(+) T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15-dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8(+) T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These fmdings suggest that CD8 memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy.