Chemokine-Regulated Recruitment of Antigen-Specific T-Cell Subpopulations to the Liver in Acute and Chronic Hepatitis C Infection

• Published in: The Journal of infectious diseases 2019-04, Vol.219 (9), p.1430-1438
• Main Authors: Pirozyan, Mehdi R, Nguyen, Nam, Cameron, Barbara, Luciani, Fabio, Bull, Rowena A, Zekry, Amany, Lloyd, Andrew R
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Antigens; Antiviral activity; Antiviral drugs; CC chemokine receptors; CCR1 protein; CCR2 protein; CCR5 protein; CCR7 protein; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Chemokine CXCL10 - metabolism; Chemokine receptors; Chemokines; Chemokines - metabolism; Chronic infection; CXCL10 protein; CXCR3 protein; Effector cells; Female; Flow cytometry; Hepatitis; Hepatitis C; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - metabolism; Hepatocytes; Humans; Immunological memory; Infections; Interferon; Leukocyte Common Antigens - metabolism; Liver; Liver - immunology; Liver - metabolism; Lymphocytes; Lymphocytes T; Male; Memory cells; Middle Aged; Monocyte chemoattractant protein 1; Peripheral blood; Receptors, CCR2 - metabolism; Receptors, CCR5 - metabolism; Receptors, CCR7 - metabolism; Receptors, Chemokine - metabolism; Receptors, CXCR3 - metabolism; Receptors, CXCR6 - metabolism
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiy679

Abstract Background In hepatitis C virus (HCV) infection, virus-specific CD8+ T cells are recruited to the liver for antiviral activity. Multiple chemokine ligands are induced by the infection, notably interferon-inducible chemokine, CXCL10. In HCV, intrahepatic T cells express chemokine receptors (CCRs), including CXCR3, CXCR6, CCR1, and CCR5, but CCR expression on antigen-specific effector and memory T cells has not been investigated. Methods Paired blood and liver samples were collected from subjects with chronic HCV for flow cytometric analysis of CCR expression on CD8+ T cells. Expression of these CCRs was then examined on HCV-specific CD8+ T-cell subpopulations in the blood from subjects with acute or chronic HCV. Results Relative to peripheral blood, the liver was enriched with CD8+ T cells expressing CCR2, CCR5, CXCR3, and CXCR6 either singly or in combinations. CXCR3 was preferentially expressed on HCV-specific CD8+ T cells in both acute and chronic phases of infection in blood. Both CXCR3 and CCR2 were overexpressed on HCV-specific CD8+CCR7+CD45RO+ (central memory) cells, whereas effector memory (CD8+CCR7−CD45RO+) cells expressed more CXCR6. Conclusions CXCR3-mediated signals support the accumulation of HCV-specific CD8+ memory T cells in the infected liver, and emphasize the importance of the CXCL10/CXCR3 trafficking pathway during acute and chronic HCV infection. Analysis of mononuclear cells from subjects with acute and chronic hepatitis C reveals that antigen-specific CD8 T cells preferentially express CXCR3. As CXCL10 is heavily expressed in the hepatitis C-infected liver, the CXCR3-CXCL10 trafficking pathway appears critical for recruitment.