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

Abstract

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 infection 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 CD8 + T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 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 findings suggest that CD8 + memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy.

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

“…Our finding that P-selectin binding cells persist into the memory phase after influenza virus infection demonstrates that, unlike for CD8 + memory cells (40), fucosylation can be maintained on CD4 + T cells after the resolution of the response, consistent with a previous report that epigenetic modifications can sustain Fut7 transcription (26). It has been suggested that maintenance of selectin binding activity could distinguish effector memory from central memory cells that have a greater capacity for self-renewal in the lymphoid compartment (10).…”

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

“…2J, K and Supplementary Tables 1 and 2). Similarly, five genes implicated in migration were DDR-regulated: GCNT1, CD44, LIMA1, CD34 and integrin 10 (ITGA10) (Wenke et al, 2006;Abe and Takeichi, 2008;Flynn et al, 2013;Nolz and Harty, 2014), but only CD34 was also VEGFA-regulated (Fig. 2J, K and Supplementary Tables 1 and 2).…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…Systemic and local inflammatory signals introduced by surgical procedures may alter the migration of circulating memory T cells as TCM cells are sensitive to inflammation-induced O-glycosylation and migration. 11 It is well documented that surgery has immediate impacts on the immune system of human patients. 79 Therefore, even as the golden standard in T RM research, the results from parabiosis experiments should be carefully interpreted along with the experiments involving less invasive procedures.…”

“…However, in contrast to the generally accepted notion that T EM cells patrol non-lymphoid tissues under steady state, recent studies have discovered that during local inflammation, T CM s, but not T EM s or long-lived effector T cells, migrate into inflamed tissues due to their superior capacity to induce O-glycosylation and generate P/E-selectin ligands, which facilitate the trans-endothelial extravasation of T cells. 10,11 Comparing with T EM , T CM cells generally express higher level of chemokine receptor CXCR3, which also enhances the migration of T CM into inflamed peripheral tissues. 12 Thus, the migration pattern of memory T cells is dynamically controlled by inflammatory signals independent of antigenic stimulation.…”