DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine

• Published in: The Journal of immunology (1950) 2015-09, Vol.195 (6), p.2861-2869
• Main Authors: Shin, Min Sun, You, Sungyong, Kang, Youna, Lee, Naeun, Yoo, Seung-Ah, Park, Kieyoung, Kang, Ki Soo, Kim, Sang Hyun, Mohanty, Subhasis, Shaw, Albert C, Montgomery, Ruth R, Hwang, Daehee, Kang, Insoo
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Adhesion - genetics; Cells, Cultured; Chemokine CX3CL1 - immunology; Chemotaxis - genetics; Chemotaxis - immunology; CX3C Chemokine Receptor 1; DNA Methylation - genetics; Humans; Immunologic Memory - immunology; Interferon-gamma - metabolism; Promoter Regions, Genetic - genetics; Receptors, Chemokine - biosynthesis; Receptors, Interleukin-7 - metabolism; T-Lymphocyte Subsets - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500877

DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells including T cells. Memory T cells are heterogeneous populations. Human effector memory (EM) CD8(+) T cells in peripheral blood contain two cell subsets with distinct traits that express low and high levels of the IL-7Rα. However, epigenetic mechanisms involved in defining such cellular traits are largely unknown. In this study, we use genome-wide DNA methylation and individual gene expression to show the possible role of DNA methylation in conferring distinct traits of chemotaxis and inflammatory responses in human IL-7Rα(low) and IL-7Rα(high) EM CD8(+) T cells. In particular, IL-7Rα(low) EM CD8(+) T cells had increased expression of CX3CR1 along with decreased DNA methylation in the CX3CR1 gene promoter compared with IL-7Rα(high) EM CD8(+) T cells. Altering the DNA methylation status of the CX3CR1 gene promoter changed its activity and gene expression. IL-7Rα(low) EM CD8(+) T cells had an increased migratory capacity to the CX3CR1 ligand fractalkine compared with IL-7Rα(high) EM CD8(+) T cells, suggesting an important biological outcome of the differential expression of CX3CR1. Moreover, IL-7Rα(low) EM CD8(+) T cells induced fractalkine expression on endothelial cells by producing IFN-γ and TNF-α, forming an autocrine amplification loop. Overall, our study shows the role of DNA methylation in generating unique cellular traits in human IL-7Rα(low) and IL-7Rα(high) EM CD8(+) T cells, including differential expression of CX3CR1, as well as potential biological implications of this differential expression.