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

J Clin Invest. 2014 Mar;124(3):1013-26. doi: 10.1172/JCI72039. Epub 2014 Feb 10.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Movement*
  • E-Selectin / metabolism
  • Glycosylation
  • Immunologic Memory
  • Inflammation
  • Interleukin-15 / physiology*
  • Lipopolysaccharides / pharmacology
  • Lung / immunology
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • P-Selectin / metabolism
  • Polysaccharides / biosynthesis*
  • Protein Processing, Post-Translational
  • Respiratory Syncytial Viruses / immunology
  • Respiratory Tract Infections / immunology
  • Respiratory Tract Infections / virology
  • Skin / immunology
  • Skin / virology
  • Toll-Like Receptors / agonists
  • Toll-Like Receptors / metabolism
  • Vaccinia virus / immunology

Substances

  • E-Selectin
  • Interleukin-15
  • Lipopolysaccharides
  • P-Selectin
  • Polysaccharides
  • Toll-Like Receptors
  • N-Acetylglucosaminyltransferases
  • beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase