Peripheral loss of <scp>CD</scp>8+<scp>CD</scp>161++<scp>TCRV</scp>α7·2+ mucosal‐associated invariant T cells in chronic hepatitis C virus‐infected patients

Barathan, Muttiah; Rosmawati, Mohamed; Vadivelu, Jamuna; Chang, Li; Saeidi, Alireza; Yong, Yean Kong; Ram, M. Ravishankar; Gopal, Kaliappan; Vijayakumar, V.; Larsson, Marie; Shankar, Esaki M.

doi:10.1111/eci.12581

Cited by 72 publications

(75 citation statements)

References 36 publications

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“…A similar loss of MAIT cells with residual MAIT cells showing an activated phenotype and loss of PLZF expression has been described in HIV and HCV infections[23–26]. None of the MAIT cells alterations that we report here were associated with the HTLV-1 proviral load and MAIT cells were not found to be infected by HTLV-1 in vivo .…”

Section: Discussionsupporting

confidence: 87%

“…MAIT cells can also be activated indirectly by IL-12 and IL18[22]. MAIT cells have been implicated in the immunopathogenesis of chronic viral infections like HIV[23, 24] and HCV[25, 26] and in inflammatory conditions like systemic lupus erythematosus[27] and MS[28, 29]. Therefore, we hypothesized that HTLV-1 infection is associated with defect in MAIT cells that could explain the increased susceptibility to Mtb.…”

Section: Introductionmentioning

confidence: 99%

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MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

et al. 2017

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HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develop HAM/TSP. The cellular immune response has been implicated in the development of inflammatory alterations in these patients; however the pathogenic mechanisms for disease progression remain unclear. Furthermore, HTLV-1-infected individuals have an increase incidence of Mycobacterium tuberculosis (Mtb) infection, suggesting that immunological defect are associated with HTLV-1 infection. Evidence suggests an important role for Mucosal-associated invariant T (MAIT) cells in the early control of Mtb infection. Chronic viral infections like HIV and HCV have been associated with decreased frequency and functionality of MAIT cells. We hypothesized that HTLV-1 infection is associated with similar perturbations in MAIT cells. We investigated MAIT cell frequency, phenotype, and function by flow cytometry in a cohort of 10 asymptomatic and 10 HAM/TSP HTLV-1 infected patients. We found that MAIT cells from HTLV-1-infected subjects were reduced and showed high co-expression of the activation markers CD38 and HLA-DR but normal levels of CCR6 and CD127. MAIT cells had a lower expression of the transcription factor PLZF in HAM/TSP patients. Unlike Tax-specific CD8+T cells, which are hyperfunctional, MAIT cells from HTLV-1-infected subjects had a poor IFNγ response following antigen stimulation. MAIT cell perturbations in HTLV-1 infection were not associated with HTLV-1 proviral load and MAIT cells were not infected by HTLV-1 in vivo. Rather, MAIT cells loss was associated with immune activation. Overall, our results do not support a role for MAIT cells in HAM/TSP pathogenesis but reduced numbers of MAIT cells, together with their poor functionality, could contribute to the increased susceptibility of HTLV-1-infected individuals to other infectious agents.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

et al. 2017

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“…Previous studies have shown that the blockade of PD-1 signalling in MAIT cells in patients with active pulmonary tuberculosis resulted in a higher frequency of MAIT cells producing IFN-γ upon bacterial stimulation 41 . An increased PD-1 expression on MAIT cells has also been associated with HIV 42 and hepatitis C 24 . In contrast to MAIT cells, conventional CD4 + and CD8 + T cells expressed higher levels of PD-1 in IVB compared to PB.…”

Section: Discussionmentioning

confidence: 99%

“…Upon stimulation, MAIT cells react by secreting interferon-γ (IFN-γ), tumour necrosis factor-α, and IL-17 16, 21 , as well as mediate cytotoxic effects via granzyme B (GrzB) and perforin 22 . Low numbers of systemic MAIT cells have been associated with severe systemic diseases, especially during bacterial infections 17, 23 , and their function has been shown to be impaired in patients with chronic viral infections, such as hepatitis and HIV 24, 25 .…”

Section: Introductionmentioning

confidence: 99%

MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation

Solders

Gorchs

Erkers

et al. 2017

Sci Rep

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During pregnancy, the maternal immune system must tolerate the developing foetus, and yet retain a potent antimicrobial response to prevent infections. Mucosal associated invariant T (MAIT) cells recognize microbial-derived vitamin B metabolites presented on the MR1 molecule, but their presence and function at the foetal-maternal interface is not known. We here isolated mononuclear cells from paired samples of peripheral blood (PB), intervillous blood (IVB), and decidua parietalis (DP) following uncomplicated term pregnancies. Interestingly, MAIT cells were highly enriched in IVB compared to PB and DP. The activation status of IVB MAIT cells was similar to that of PB MAIT cells, except for a lower expression of PD-1. Both IVB MAIT cells and conventional T cells were more dominated by an effector memory phenotype compared to PB MAIT cells and T cells. IVB MAIT cells also responded more vigorously with expression of IFN-γ, granzyme B, and perforin in response to Escherichia coli stimulation compared to PB. MR1 was not expressed in syncytiotrophoblasts, but in placental villous and decidual macrophages. These data indicate that maternal MAIT cells accumulate in the intervillous space of the placenta and that they are highly armed to quickly respond if bacteria are encountered at the foetal-maternal interface.

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“…18,61 Jo et al 18 found that MAIT cells were enriched in normal and chronically hepatitis B virus-infected livers but were relatively depleted in endstage liver disease. Billerbeck et al 17 found that CD161 ++ CD8 + cells (probably MAIT cells) had higher capacity for IL-17 and IL-22 production in the liver compared with the peripheral blood and that dual functionality (ability to co-express IL-17 and IFN-c upon stimulation) of these cells was inversely correlated with clinical disease score in chronic untreated hepatitis C. In the peripheral compartment, Barathan et al 62 found that patients with chronic HCV had lower MAIT cells frequencies compared with healthy controls. Likely reflecting a state of chronic inflammation and infection, MAIT cells in these patients had higher levels of markers of activation and exhaustion (HLA-DR, CD38, PD-1, TIM-3 and CTLA-4) compared with healthy controls.…”

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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Peripheral loss of CD8⁺CD161⁺⁺TCRVα7·2⁺ mucosal‐associated invariant T cells in chronic hepatitis C virus‐infected patients

Abstract: Immune exhaustion and senescence of CD8(+) CD161(++) TCR Vα7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.

Cited by 72 publications

References 36 publications

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation

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

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Peripheral loss of CD8+CD161++TCRVα7·2+ mucosal‐associated invariant T cells in chronic hepatitis C virus‐infected patients

Abstract: Immune exhaustion and senescence of CD8(+) CD161(++) TCR Vα7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.

Cited by 72 publications

References 36 publications

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation

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

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Resources

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Peripheral loss of CD8⁺CD161⁺⁺TCRVα7·2⁺ mucosal‐associated invariant T cells in chronic hepatitis C virus‐infected patients