CD4⁺Foxp3⁺ T cells promote aberrant immunoglobulin G production and maintain CD8⁺ T-cell suppression during chronic liver disease

• Type of Material: Article
• Authors: Dana Tedesco, Emory University; Manoj Thapa, Emory University; Sanjeev Gumber, Emory University; Elizabeth J. Elrod, Emory University; Khalidur Rahman, Emory University; Chris Ibegbu, Emory University; Joseph F. Magliocca, Emory University; Andrew Adams, Emory University; Frank A Anania, Emory University; Arash Grakoui, Emory University
• Language: English
• Date: 2017-02-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 by the American Association for the Study of Liver Diseases
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.28894
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 65
• Issue: 2
• Start Page: 661
• End Page: 677
• Grant/Funding Information: Immunology and Flow Cytometry Core of the Center for AIDS Research at Emory University. Grant Number: P30AI050409; Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.; National Institutes of Health. Grant Numbers: R01AI070101, R01AI124680, R01AI126890, R01 DK062092, VA I01BX001746, ORIP/OD P51OD011132; National Institute of Diabetes, Digestive and Kidney Diseases. Grant Number: F32DK101163
• Keywords: Forkhead Transcription Factors; Cells, Cultured; Liver Cirrhosis; Random Allocation; Immunoglobulin G; Flow Cytometry; Chronic Disease; Disease Models, Animal; Animals; Enzyme-Linked Immunospot Assay; Analysis of Variance; Male; CD8-Positive T-Lymphocytes; Statistics, Nonparametric; Hepatocytes; Hepatitis C, Chronic; Immunohistochemistry; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Enzyme-Linked Immunosorbent Assay; Humans
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T-cell responses. In light of dampened CD8 + T-cell responses, liver disease often manifests systemically as immunoglobulin (Ig)-related syndromes due to aberrant B-cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4 + T-cell help. Elevated CD4 + forkhead box P3–positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8 + T-cell responses, aberrant B-cell activities were maintained due to expression of CD40 ligand on a subset of CD4 + Foxp3+ T cells. In vivo blockade of CD40 ligand attenuated B-cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4 + Foxp3+, CD40 ligand–positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. Conclusion: Liver disease elicits alterations in the intrahepatic CD4 + T-cell compartment that suppress T-cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (Hepatology 2017;65:661-677).