Daniela C Kroy1, Donatella Ciuffreda1, Jennifer H Cooperrider1, Michelle Tomlinson2, Garrett D Hauck1, Jasneet Aneja1, Christoph Berger3, David Wolski1, Mary Carrington4, E John Wherry5, Raymond T Chung1, Kenneth K Tanabe6, Nahel Elias7, Gordon J Freeman8, Rosemarie H de Kruyff9, Joseph Misdraji10, Arthur Y Kim11, Georg M Lauer12. 1. Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 2. Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 3. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts. 4. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts; Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 5. Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 6. Divison of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 7. Transplantation Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 8. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. 9. Division of Immunology, Children's Hospital and Harvard Medical School, Boston, Massachusetts. 10. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 11. Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 12. Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: glauer@mgh.harvard.edu.
Abstract
BACKGROUND & AIMS: There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections. METHODS: We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virological responses to treatment, and 1 from a patient with spontaneous clearance) with 19 paired blood samples and 51 liver samples from HCV-negative patients with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified for total and virus-specific T cells by flow cytometry. RESULTS: Levels of the markers PD-1 and 2B4 (but not CD160, TIM-3, or LAG-3) were increased on intrahepatic T cells from healthy and diseased liver tissues compared with T cells from blood. HCV-specific intrahepatic CD8(+) T cells from patients with chronic HCV infection were distinct in that they expressed TIM-3 along with PD-1 and 2B4. In comparison, HCV-specific CD8(+) T cells from patients with sustained virological responses and T cells that recognized cytomegalovirus lacked TIM-3 but expressed higher levels of LAG-3; these cells also had different memory phenotypes and proliferative capacity. CONCLUSIONS: T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and cytomegalovirus-specific CD8(+) T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.
BACKGROUND & AIMS: There is an unclear relationship between inhibitory receptor expression on T cells and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is often not the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver T cells from patients with hepatitis C virus (HCV) and other viral infections. METHODS: We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virological responses to treatment, and 1 from a patient with spontaneous clearance) with 19 paired blood samples and 51 liver samples from HCV-negative patients with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified for total and virus-specific T cells by flow cytometry. RESULTS: Levels of the markers PD-1 and 2B4 (but not CD160, TIM-3, or LAG-3) were increased on intrahepatic T cells from healthy and diseased liver tissues compared with T cells from blood. HCV-specific intrahepatic CD8(+) T cells from patients with chronic HCV infection were distinct in that they expressed TIM-3 along with PD-1 and 2B4. In comparison, HCV-specific CD8(+) T cells from patients with sustained virological responses and T cells that recognized cytomegalovirus lacked TIM-3 but expressed higher levels of LAG-3; these cells also had different memory phenotypes and proliferative capacity. CONCLUSIONS: T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and cytomegalovirus-specific CD8(+) T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.
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