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Hepatology Snapshot
T cell regulation in HBV-related chronic liver disease
Carlo Ferrari, , , Carolina Boni, Marzia Rossi, Andrea Vecchi, Valeria Barili, Diletta Laccabue, Paola Fisicaro, Gabriele Missale
Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria di Parma, and Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
Received 23 August 2016, Revised 3 October 2016, Accepted 3 October 2016, Available online 8 February 2017
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http://doi.org/10.1016/j.jhep.2016.10.002
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HBV-specific T cell dysfunction is believed to play a central role in the pathogenesis of chronic HBV persistence [1] ; [2]. HBV-specific T cells are more dysfunctional within the liver than in the periphery [3] as a result of the inhibitory effect of different mechanisms. They are likely to be active simultaneously within the inflamed liver together contributing to T cell functional impairment [4] ; [5]. Some of them have been directly characterized in HBV infection, while others are assumed to be relevant because of their general importance within the liver.
Panel A. Persistent exposure to high antigen load within the liver and in the periphery can cause HBV-specific T cell exhaustion and deletion
High antigen loads and high frequencies of infected liver cells are constantly detectable in chronically HBV infected patients [1] resulting in persistent antigen exposure, which is a key feature of T cell exhaustion in chronic HBV infection. Chronic antigen stimulation is associated with sustained expression of programmed death 1 (PD-1) and other co-inhibitory molecules on HBV-specific T cells, including TIM-3, CTLA-4, 2B4, CD160, LAG-3, etc., [1]; [2] ; [3]. Although co-inhibitory molecules can be weakly and transiently expressed on functionally efficient T cells as a result of activation, their high and sustained expression is the hallmark of T cell exhaustion [6]. Upregulation of the corresponding ligands has been observed on liver resident and infiltrating cells during chronic liver inflammation [1]; [2] ; [7]. Thus, constant T cell receptor stimulation and continuous exposure to inhibitory ligands can contribute to T cell exhaustion.
Once HBV-specific T cells reach the liver, they are subjected to the inhibitory effect of the hepatic microenvironment where an excess of arginase and indoleamine 2,3-dioxygenase (IDO) can induce depletion of important nutrients needed for T cell proliferation and function, as well as an accumulation of toxic metabolites which can further impair T cell responses [4] ; [7].
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