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

Dana Tedesco, Manoj Thapa, Sanjeev Gumber, Elizabeth J. Elrod, Khalidur Rahman, Chris C. Ibegbu, Joseph F. Magliocca, Andrew B. Adams, Frank Anania, Arash Grakoui

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5 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)661-677
Number of pages17
JournalHepatology
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

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    Tedesco, D., Thapa, M., Gumber, S., Elrod, E. J., Rahman, K., Ibegbu, C. C., Magliocca, J. F., Adams, A. B., Anania, F., & Grakoui, A. (2017). CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology, 65(2), 661-677. https://doi.org/10.1002/hep.28894