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.
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.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Min Sun
MS
Shin
Division of Cancer Biology and Therapeutics, Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Division of Cancer Biology and Therapeutics, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Division of Cancer Biology and Therapeutics, Department of Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
Sungyong
S
You
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Youna
Y
Kang
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Naeun
N
Lee
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Seung-Ah
SA
Yoo
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Pediatrics, College of Medicine, Ulsan University, Ulsan 680-749, Republic of Korea;
Kieyoung
K
Park
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Pediatrics, Jeju National University School of Medicine, Jeju 690-756, Republic of Korea;
Ki Soo
KS
Kang
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Microbiology, College of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea;
Sang Hyun
SH
Kim
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Subhasis
S
Mohanty
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Albert C
AC
Shaw
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Ruth R
RR
Montgomery
School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang 790-784, Republic of Korea; and Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu Gyeongbuk Institute of Science & Technology, Daegu, 711-873, Republic of Korea.
Daehee
D
Hwang
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Insoo.kang@yale.edu.
Insoo
I
Kang
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000276:immunology*; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine; D020395:Receptors, Interleukin-7; D014409:Tumor Necrosis Factor-alpha; C415350:interleukin-7 receptor, alpha chain; D007371:Interferon-gamma