Frequencies of Circulating MAIT Cells Are Diminished in Chronic HCV, HIV and HCV/HIV Co-Infection and Do Not Recover during Therapy

Spaan, Michelle; Hullegie, Sebastiaan J.; Beudeker, Boris J.B.; Kreefft, Kim; Oord, Gertine W. van; Groothuismink, Zwier M. A.; Tilborg, Marjolein van; Rijnders, Bart J. A.; Knegt, Robert J. de; Claassen, Mark A. A.; Boonstra, André

doi:10.1371/journal.pone.0159243

Cited by 56 publications

(69 citation statements)

References 34 publications

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“…1A). Consistent with previous reports 15, 20, 22 , the frequency of MAIT cells was lower in the blood of patients with chronic HCV infection than of uninfected controls (1.31%, interquartile range [IQR] 0.61%–1.92% vs 2.32%, IQR 0.96%–3.5%; P =.0048, Fig. 1B left panel).…”

Section: Resultssupporting

confidence: 91%

“…It is also consistent with the increase in the frequency of MAIT cells in the liver along with the resolution of liver inflammation by week four of antiviral therapy. In contrast, and consistent with previous reports 15, 20, 22 , antiviral therapy did not improve the reduced MAIT cell frequency in the peripheral blood even during a longer follow up to week 24 post therapy. Since the liver is equipped with a high density of immune cells, an increase in MAIT cell frequency in the blood may lag significantly behind any changes the liver.…”

Section: Discussionsupporting

confidence: 91%

“…MAIT cells can be activated by cytokines such as type I IFN 15 , IL-7 16 , IL-12 and IL-18 17 . The levels of many of these cytokines are increased in the blood and the liver of HCV-infected patients 18, 19 .…”

Section: Introductionmentioning

confidence: 99%

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Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation

et al. 2017

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Background & Aims Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal associated invariant T (MAIT) cells are enriched in the liver as compared to the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy. Methods We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation. Results The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median 1.31% vs 2.32% for blood samples, P=.0048 and median 4.34% vs 13.40% for liver samples, P=.001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r=−.5437, P=.0006) and fibrosis (r=−.5829, P=.0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P<.0001). Production of interferon gamma (IFNG) by MAIT cells was dependent on monocyte-derived interleukin 18 (IL18), and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared to controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy. Conclusions In analyses of paired blood and liver samples from patients with chronic HCV infection before, during and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

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Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation

et al. 2017

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“…The reduction of circulating MAIT cells was also reported in patients with chronic viral infections, including human immunodeficiency virus and hepatitis C virus, although we could not identify this reduction of MAIT cells in the blood of patients with CVH. We could not determine the reason for the discrepancy between previous studies and our study; however, the median value of ALT in the patients with CVH in our study seems to be lower than that in patients with hepatitis C virus infection in the previous studies . We speculate that our study included patients with less active liver inflammation and that MAIT cells might be less activated.…”

Section: Discussionmentioning

confidence: 99%

Persistent reduction of mucosal‐associated invariant T cells in primary biliary cholangitis

Setsu

Yamagiwa

Tominaga

et al. 2018

J of Gastro and Hepatol

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“…Two recent studies in HCV-infected patients have similarly found that the MAIT cell depletion and dysfunction observed in chronic HCV is not reversible even after successful interferon therapy or interferon-free therapy. 63,64 The role of MAIT cells in liver inflammation and the impact of MAIT cell perturbations on the general state of mucosal immunity in patients with these infections require further investigation.…”

Section: Mait Cells and Viral Hepatitismentioning

confidence: 99%

The role of mucosal‐associated invariant T cells in infectious diseases

2016

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SummaryMucosal-associated invariant T (MAIT) cells are donor-unrestricted lymphocytes that are surprisingly abundant in humans, representing 1-10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC-related antigen-presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti-bacterial immunity at mucosal interfaces. Some fungi are known to produce MAIT-activating ligands, but the role of MAIT cells in fungal infections has not yet been investigated. In viral infections, specifically HIV, which has received the most study, MAIT cell biology is clearly altered, but the mechanisms explaining these alterations and their clinical significance are not yet understood. Many questions remain unanswered about the potential of MAIT cells for protection or pathogenesis in infectious diseases. Because they interact with the universal, donor-unrestricted ligand-presenting MR1 molecule, MAIT cells may be attractive immunotherapy or vaccine targets. New tools, including the development of MR1-ligand tetramers and next-generation T-cell receptor sequencing, have the potential to accelerate MAIT cell research and lead to new insights into the role of this unique set of lymphocytes in infectious diseases.

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Frequencies of Circulating MAIT Cells Are Diminished in Chronic HCV, HIV and HCV/HIV Co-Infection and Do Not Recover during Therapy

Cited by 56 publications

References 34 publications

Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation

Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation

Persistent reduction of mucosal‐associated invariant T cells in primary biliary cholangitis

The role of mucosal‐associated invariant T cells in infectious diseases

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