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
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]. 作者: StephenW 时间: 2017-4-16 21:25
Panel B. Liver suppressive environment: Increased arginase activity
The main source of arginase can be from damaged hepatocytes and liver infiltrating cells, such as myeloid-derived suppressor cells. These are expanded particularly in those chronic patients with high HBV replication levels and a lack of overt immunopathology [8]. An excess of arginase results in the depletion of the amino acid arginine. Deprivation of arginine is reflected by the downregulation of CD3ζ and leads to the suppression of functional T cells proliferation.
Panel C. Liver suppressive environment: Increased IDO/TDO expression
A number of liver infiltrating cells, including monocytes, macrophages and dendritic cells upon IFN-γ stimulation can produce IDO [3]; [4] ; [6], which can cause tryptophan depletion with subsequent inhibition of T cell proliferation and function. Tryptophan metabolism can also give rise to toxic compounds, such as kynurenines, which are responsible for T cell apoptosis and differentiation of CD4 cells in Treg cells [9].
Panel D. Liver suppressive environment: Hyperexpression of regulatory cytokines
Expanded regulatory T cells (Treg) cells contribute to create a local intrahepatic suppressive cytokine milieu by secreting interleukin (IL)-10 and transforming growth factor beta (TGF-β). These suppressive soluble mediators can also be produced by other cell types. Stellate cells can secrete TGF-β while dendritic cells, Kupffer cells and B cells secrete IL10 [3] ; [4].
Panel E. Mechanisms of Treg expansion within the liver
Expansion of Treg cells can inhibit T cell responses either by direct cell-cell contact or by secretion of suppressive cytokines. This expansion can also be caused by plasmacytoid dendritic cells (pDC) through an IL27-based circuit, which can lead to PD-L1 expression, with subsequent Treg proliferation. Treg cell expansion can be also stimulated by IFN-γ activated liver sinusoidal endothelial cells (LSEC) and stellate cells in a PD-L1 independent manner [3] ; [4].作者: StephenW 时间: 2017-4-16 21:27
Panel F. Activated natural killer (NK) cells can delete HBV-specific T cells in chronic HBV infection
The intrahepatic suppressive cytokine milieu can impair not only the T cell function but also NK cells, which are abundant within the liver and barely able to produce IFN-γ in chronic HBV patients [10]; [11] ; [12]. Instead, NK cells can show efficient cytolytic activity and upregulate the death ligand TNF-related apoptosis-inducing ligand (TRAIL) [11] ; [12]. TRAIL can engage with the upregulated TRAIL-R2 receptor on liver cells, thereby amplifying liver damage [11] ; [12]. TRAIL positive NK cells can also interact with TRAIL-R2 positive HBV-specific T cells and delete them, thereby contributing to HBV-specific T cell attrition [11] ; [12]. T cell susceptibility to apoptotic death can be amplified by the upregulation of the pro-apoptotic BIM molecule in HBV-specific T cells (see panel A) [7].
Panel G. Myeloid cell plasticity
Myeloid cells also play a key regulatory role within the liver because they can differentiate from monocytes into macrophages, monocyte-derived dendritic cells or myeloid suppressor cells, thanks to their functional plasticity. During liver inflammation, inflammatory monocytes can be recruited into the liver as a result of intercellular adhesion molecule 1 (ICAM-1 [CD54]) expression on LSEC [4]. They can then differentiate into myeloid-derived suppressor cells by a CD44-dependent mechanism driven by activated stellate cells [4]. On the other hand, TLR-9 signaling can drive monocyte differentiation towards anti-viral protection by causing the formation of inflammatory monocyte aggregates, called iMATEs, where virus-specific CD8 cells can expand upon OX40 and CD28 signaling released from inflammatory dendritic cells of monocyte origin [13].
Panel H. T cell activation by liver antigen presenting cells (APC) is suboptimal and can promote tolerance
Several liver cell types, including LSEC, stellate cells and Kupffer cells can serve as APC to activate naive T cells [14]. Interestingly, CD8 T cells can extend protrusions through fenestra in LSEC to sample HBV antigens on hepatocytes [15]. T cell activation within the liver can be however suboptimal with tolerance induction because most of these hepatic APC show very poor expression of co-stimulatory molecules in the steady state, express increased levels of the co-inhibitory molecules PD-L1 and PD-L2 upon IFN stimulation and can produce immune regulatory cytokines, including IL10 and TGF-β.
Financial support
This work was supported by a grant from Regione Emilia-Romagna, Italy (Programma di Ricerca Regione-Università 2010-2012; PRUa1RI-2012-006) and by a FIRB grant (RBAP10TPXK) from the Italian Ministry of University and Research.
Conflict of interest
Carlo Ferrari: research grants from Gilead, Roche and Janssen, served as advisor/consultant for Gilead, Merck, Abbvie, BMS and Arrowhead.
Gabriele Missale: served as consultant for Bayer.作者: StephenW 时间: 2017-4-16 21:28