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Cells. 2019 Apr 25;8(4). pii: E374. doi: 10.3390/cells8040374.

Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8+ T-Cell Dysfunction.

Ahmed F1,2, Ibrahim A3,4, Cooper CL5,6,7, Kumar A8,9, Crawley AM10,11,12,13.

Author information

1
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. fahme097@uottawa.ca.
2
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. fahme097@uottawa.ca.
3
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. andibrahim@ohri.ca.
4
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. andibrahim@ohri.ca.
5
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. ccooper@toh.ca.
6
Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada. ccooper@toh.ca.
7
Public Health and Preventative Medicine, School of Epidemiology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1G 5Z3, Canada. ccooper@toh.ca.
8
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. akumar@uottawa.ca.
9
Department of Pathology, The Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada. akumar@uottawa.ca.
10
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. acrawley@ohri.ca.
11
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. acrawley@ohri.ca.
12
Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada. acrawley@ohri.ca.
13
Department of Biology, Faculty of Science, Carleton University, Ottawa, ON K1S 5B6, Canada. acrawley@ohri.ca.

Abstract

Chronic hepatitis C virus (HCV) infection causes generalized CD8+ T cell impairment, not limited to HCV-specific CD8+ T-cells. Liver-infiltrating monocyte-derived macrophages (MDMs) contribute to the local micro-environment and can interact with and influence cells routinely trafficking through the liver, including CD8+ T-cells. MDMs can be polarized into M1 (classically activated) and M2a, M2b, and M2c (alternatively activated) phenotypes that perform pro- and anti-inflammatory functions, respectively. The impact of chronic HCV infection on MDM subset functions is not known. Our results show that M1 cells generated from chronic HCV patients acquire M2 characteristics, such as increased CD86 expression and IL-10 secretion, compared to uninfected controls. In contrast, M2 subsets from HCV-infected individuals acquired M1-like features by secreting more IL-12 and IFN-γ. The severity of liver disease was also associated with altered macrophage subset differentiation. In co-cultures with autologous CD8+ T-cells from controls, M1 macrophages alone significantly increased CD8+ T cell IFN-γ expression in a cytokine-independent and cell-contact-dependent manner. However, M1 macrophages from HCV-infected individuals significantly decreased IFN-γ expression in CD8+ T-cells. Therefore, altered M1 macrophage differentiation in chronic HCV infection may contribute to observed CD8+ T-cell dysfunction. Understanding the immunological perturbations in chronic HCV infection will lead to the identification of therapeutic targets to restore immune function in HCV+ individuals, and aid in the mitigation of associated negative clinical outcomes.

KEYWORDS:

CD8+ T-cells; hepatitis C virus; interferon-γ; macrophages; monocyte-derived macrophages

PMID:
31027182
DOI:
10.3390/cells8040374
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