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 4

Intranasal challenge with TLR agonists recruits memory CD8+ T cells that express core 2 O-glycans.

Options: View larger image (or click on image) Download as PowerPoint
Intranasal challenge with TLR agonists recruits memory CD8+ T cells that...
(A) 1 × 106 purified memory Thy1.1 P14 CD8+ T cells were transferred into naive B6 (Thy1.2) mice. One day later, mice were challenged intranasally with CpG. At 12, 36, and 60 hours following CpG challenge, expression of core 2 O-linked glycosylated CD43 (1B11) was analyzed on memory P14 CD8+ T cells in the lung. (B) Quantification of expression shown in A. (C) Quantification of total memory P14 CD8+ T cells in the lung 60 hours following challenge from A. (D) Same as in A, with the exception that at 60 hours following CpG challenge, the frequency of Thy1.1 memory P14 CD8+ T cells was analyzed in the blood, spleen, and lung. (E) Same as in A, with the exception that proliferation of memory P14 CD8+ T cells in the lung was determined by BrdU incorporation. (F) Same as in A, with the exception that mice were challenged with LPS. (G) Quantification of total memory P14 CD8+ T cells from F. (H) Expression of core 2 O-linked glycosylated CD43 on P14 CD8+ T cells in the lungs from mice that received saline (shaded histogram; bottom number) or LPS (unfilled histogram; top number). Numbers indicate percentages of memory CD8+ T cells that express glycosylated CD43. Data are representative of 3 or more independent experiments, and statistical analysis used the Student’s t test.