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.
View: Text | PDF
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

×

Figure 5

P- and E-selectin interactions are required for memory CD8+ T cell recruitment to inflamed tissues.

Options: View larger image (or click on image) Download as PowerPoint
P- and E-selectin interactions are required for memory CD8+ T cell recru...
(A) 1 × 106 purified memory P14 CD8+ T cells (Thy1.1) were transferred into naive B6 mice (Thy1.2) that were then challenged intranasally with either saline or CpG. Three days after challenge, memory P14 CD8+ T cells in the lung were analyzed for coexpression of core 2 O-linked glycosylated CD43 (1B11) and the ability to bind to either P- or E-selectin. (B and C) 1 × 106 memory P14 CD8+ T cells were transferred into naive B6 mice followed by intranasal challenge with either saline or CpG. On day 3 after challenge, total memory P14 CD8+ T cells in the lungs were quantified in mice that received i.v. administration of an isotype control antibody or blocking antibodies against either (B) P- and E-selectin or (C) PSGL-1. (D) Mice containing memory P14 CD8+ T cells were generated as in Figure 3 and infected on the left ear with VacV-GP33. Total P14 CD8+ T cells in the ears were quantified on day 3 after infection in mice receiving an isotype control or P- and E-selectin–blocking antibodies. (E) Same as in D, with the exception that viral burden of the ear was determined on day 4 after infection. Data are representative of 2 or more independent experiments, and statistical analysis used 1-way ANOVA with a Bonferroni post-test for multiple comparisons.