MAIT be different–persisting dysfunction after DAA‐mediated clearance of chronic hepatitis C virus infection

Abstract

MAIT cells are an abundant innate-like T-cell subset that is defined by the invariant T-cell receptor (iTCR) V-alpha chain Vα7.2-Jα33. Little is currently known about their frequency and function in chronic hepatitis C virus (HCV) infection and their fate after therapy-mediated HCV elimination by direct acting antivirals (DAA). In this issue of theMAIT cells are an abundant innate-like T-cell subset that is defined by the invariant T-cell receptor (iTCR) V-alpha chain Vα7.2-Jα33 [9,10]. Human MAIT cells comprise about 5-10% of T cells within the periphery and are enriched in the gut and liver, where they may represent between 12 and 50% of T cells. They are phenotypically characterized by a high expression of the C-type lectin CD161, the dipeptidase CD26 and the IL-18Rα. In terms of function, MAIT cells are capable of secreting multiple cytokines such as IL-17, IFN-γ, and TNF-α, and of performing cytotoxic effector functions [9,10]. The specific phenotype of MAIT cells is largely influenced by the transcription factors RORγt and PLZF [11,12]. Specifically, both transcription factors have been associated with high-level expression of CD161 and IL-18Rα. High expression levels of Helios complete the transcriptional signature so far known for MAIT cells [13]. The iTCR expressed by MAIT cells primarily recognizes bacterial metabolites presented by the MHC class I-related molecule 1 (MR1), and thus, most studies have examined their potential biological role in bacterial infections [14]. For example, a protective role of MAIT cells in M. tuberculosis has been reported [15]. However, there is also growing evidence that MAIT cells may contribute to antiviral immunity. Indeed, a recent study by the group of Paul Klenerman has shown that MAIT cells are activated during human viral infections with dengue virus, influenza virus, and HCV [16]. This activation is TCR-independent but depends on cytokines, primarily IL-18. Thus, MAIT cells might amplify immune responses even in the absence of antigen recognition. Noteworthy, in the case of HCV, a direct IFN-γ-mediated inhibitory effect of cytokine-activated MAIT cells on viral replication has also been shown in vitro [16].In chronic HCV infection, however, MAIT cells have been shown to be present only at low frequencies [16]. Indeed, Hengst et al. [8] even found that MAIT cells are the most affected immune cell type in the peripheral blood and that this did not correlate with alterations in other analyzed immune cells or clinical parameters such as liver disease. Circulating MAIT cells in HCV patients also displayed an altered phenotype with increased expression of CD69, HLA-DR, and PD-1 and lower expression levels of CD127 [8]. This was accompanied by reduced PLZF and Helios expression. In addition, MAIT cells are impaired in their MR-1-dependent effector functions: Contrary to healthy donors, MAIT cells obtained from chronically HCV-infected patients showed a decreased activation, cytokine production (IFN-γ, TNF, and IL-17) and degranulation after stimulation with E. coli. MR-...

Baseline and Breakthrough Resistance Mutations in HCV Patients Failing DAAs

“…Therefore, since RASs detected by deep sequencing analysis were comparable between responder and treatment-failing patients (60% vs 66.7%), and only 13.3% of additional patients would have failed treatment in the group of patients failing DAAs, systematic deep sequencing analysis is currently not recommended 21 . The role of natural resistance is still controversial due to the high SVR rates, and to date it is relevant only for selected NS3-NS5A inhibitors 28 – 30 , in selected HCV genotypes and clinical settings. Deep analysis on the incidence of RASs at the baseline performed in a larger group of SVR showed that direct sequencing with 15% cut off was able to detect most clinically relevant baseline RASs 21 .…”

Virus-Mediated Suppression of the Antigen Presentation Molecule MR1

“…Recently, it has become clear that viral infection can modulate both circulating MAIT cell number and function (Barathan et al, 2016;Cosgrove et al, 2013;Eberhard et al, 2014;Fernandez et al, 2015;Hengst et al, 2016;Hofmann and Thimme, 2016;Paquin-Proulx et al, 2017;Vinton et al, 2016), and MAIT cells can be activated by viral infection; however, this is driven in an MR1independent fashion by cytokines, including interleukin-12 (IL-12) and IL-18 Paquin-Proulx et al, 2018;van Wilgenburg et al, 2016). There have been no reports of a link between viral infection and modulation of MR1.…”

Viral Hepatitis and Hepatocellular Carcinoma: State of the Art

“…Strunz et al reported a reduced NK cell surface receptor repertoire in HCV infected individuals which persisted well beyond curative treatment [102]. Similar further results were found in mucosal associated invariant T cells, where both reduced numbers and functionality were observed even after successful DAA treatment [113]. Finally, Treg cell numbers remain increased following DAA treatment further limiting the overall functionality of the immune response [114].…”