IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking
Jeffrey C. Nolz, John T. Harty
Jeffrey C. Nolz, John T. Harty
Published February 10, 2014
Citation Information: J Clin Invest. 2014;124(3):1013-1026. https://doi.org/10.1172/JCI72039.
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Research Article Immunology

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.

Authors

Jeffrey C. Nolz, John T. Harty

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Figure 8

Regulation of Gcnt1 expression in antigen-specific CD8+ T cells following infection.

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Regulation of Gcnt1 expression in antigen-specific CD8+ T cells followin...
(A) The core 1 O-glycan structure originating from a serine or threonine amino acid (S/T) is formed by the addition of galactose in a β1-3 linkage to N-acetylgalactosamine. Generation of the core 2 structure occurs following activity of one of three core 2 β1,6-N-acetylglucosaminyltransferases (C2GlcNAcT) on the core 1 structure. Subsequent activity by other glycotransferases ultimately results in core 2 O-glycan extension and generation of the sialyl Lewis X. (B) Core 1 O-glycan expression (binding of the lectin jacalin) of P14 CD8+ T cells following LCMV infection. (C) Quantification of Gcnt1, Gcnt3, and Gcnt4 mRNA in naive, effector (day 5 after infection), and memory (day 75 after infection) P14 CD8+ T cells following LCMV infection. Changes in gene expression were determined using Hprt as a reference gene. (D) Naive, effector, and memory P14 CD8+ T cells were purified, and Gcnt1 expression was determined by immunoblot. (E) Using transcript variant-specific 5′ primers, only expression of Gcnt1 transcript variant 1 could be detected in antigen-specific CD8+ T cells following LCMV infection. (F) Enrichment of trimethylated lysine 27 (H3K27me3) and trimethylated lysine 4 (H3K4me3) histone H3 modifications at the Gcnt1 promoter region in naive and memory CD8+ T cell populations. Values on the x axis indicate the median position of the amplified region of DNA relative to the transcription start site of Gcnt1 variant 1. Data are representative of 2 or more independent experiments.