Arming of MAIT Cell Cytolytic Antimicrobial Activity Is Induced by IL-7 and Defective in HIV-1 Infection

Leeansyah, Edwin; Svärd, Jenny; Dias, Joana; Buggert, Marcus; Nyström, Jessica; Quigley, Máire F.; Moll, Markus; Sönnerborg, Anders; Nowak, Piotr; Sandberg, Johan K.

doi:10.1371/journal.ppat.1005072

Cited by 195 publications

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“…In chronic HIV-1 infection MAIT cells experience changes in these transcription factors [8]. In particular, the combined loss of T-bet and Eomes was strongly linked to the functional impairment of MAIT cells [8]. In the present HCV cohort, we did not observe loss of T-bet and Eomes in MAIT cells (Fig.…”

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 51%

“…The MAIT cell-dysfunction in HIV-1 can be partly rescued upon successful anti-retroviral therapy or IL-7 stimulation in vitro [8,29]. To assess if MAIT cell function was restored upon successful IFN-free therapy, we compared matched samples taken before treatment and 36 weeks after treatment initiation.…”

Section: Mr1-dependent Mait-cell Responses Are Impaired In Chronic Hcmentioning

confidence: 99%

“…Similarly, T-bet and Eomes were downregulated in antigen-specific CD8 T cells during chronic HCV-infection [37]. MAIT cells are distinct among T cells in that they express transcription factors for multiple effector programs including PLZF, T-bet, Eomes, and Helios, albeit some, including T-bet at low levels [8]. In chronic HIV-1 infection MAIT cells experience changes in these transcription factors [8].…”

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 99%

“…MAIT cells are distinct among T cells in that they express transcription factors for multiple effector programs including PLZF, T-bet, Eomes, and Helios, albeit some, including T-bet at low levels [8]. In chronic HIV-1 infection MAIT cells experience changes in these transcription factors [8]. In particular, the combined loss of T-bet and Eomes was strongly linked to the functional impairment of MAIT cells [8].…”

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 99%

“…Since the TCRs expressed by MAIT cells recognize bacterial metabolites presented by MHC-related protein 1 (MR1) [1,2], these cells have mainly been studied in the context of bacterial infections, where they contribute to protection [3][4][5]. However, MAIT cells are also responsive to cytokines such as IL-7, IL-12, and IL-18, suggesting that they also participate in host responses to viral infections [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction Mucosal-associated invariant T (MAIT) cells are T cells with innate-like characteristics enriched in human liver and at mucosalCorrespondence: Dr. Niklas K. Björkström e-mail: niklas.bjorkstrom@ki.se sites [1,2]. They express a semi-invariant TCR carrying the Vα7.2 segment together with a restricted Vβ repertoire [1,2]. Upon activation, MAIT cells respond rapidly with cellular cytotoxicity as well as secretion of proinflammatory and anti-viral cytokines such * These authors contributed equally to this work. HCV is an extremely successful pathogen in that it establishes chronic infection in up to 90% of infected humans [9]. The reasons behind the failure of the human immune system to clear HCV are not fully understood but involve viral escape, CD4 and CD8 T-cell exhaustion, as well as NK-cell dysfunction [10][11][12] Until recently, pegylated IFN-α together with ribavirin was used to treat chronic HCV-infection. However, pegylated IFN-α in doses administered to patients has direct inhibitory effects on immune cells [15][16][17][18]. In the last years, treatment of HCV has undergone a revolution with the introduction of highly effective direct-acting antivirals (DAA) that rapidly eliminate the virus [19]. Thus, today the vast majority of patients clear HCV after such IFN-free treatment regimens. This remarkable outcome allows for studies on consequences on immune cell recovery following rapid pathogen removal. In such studies, it was recently shown that both HCVspecific CD8 T cell and NK-cell populations become reinvigorated following viral clearance [20][21][22][23]. However, whether MAIT cells recover upon HCV clearance remains unclear.Here, we performed a comprehensive analysis of MAIT cells in chronic HCV-infection. Specifically, we addressed whether MAIT cell recovery occurs upon HCV-clearance in patients receiving an IFN-free treatment regimen consisting of sofosbuvir and ribavirin. Strikingly, and in contrast to other immune cells, MAIT cells were not reinvigorated following successful HCV-clearance using IFNfree therapy. The results are discussed in relation to the current knowledge on human MAIT cell responses to other viral infections and in the context of immune exhaustion during chronic infections. Results and discussion MAIT cells are among the most severely affected immune cells in chronic HCV-infectionTo determine the impact of chronic HCV-infection on the peripheral blood immune cell compartment, we assessed the major myeloid and lymphoid immune cell subsets in a cohort of HCVpatients and healthy donors by using a 23-parameter flow cytometry staining approach as previously described [24] (Supporting Information Fig. 1). The major phenotype observed in chronic HCV was a severe loss of MAIT cells (Fig. 1A, B). Other immune cell alterations noted were in line with previous studies, including an increase in Tregs [25], a reduced frequency of pDCs [26], and a shift within the CD4...

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Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 51%

Section: Mr1-dependent Mait-cell Responses Are Impaired In Chronic Hcmentioning

confidence: 99%

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 99%

Section: Alterations In Mait Cell Transcription Factor Expression In mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

et al. 2016

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MAIT cells as attractive vaccine targets

2019

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Mucosal‐associated invariant T (MAIT) cells are a subset of T cells that perform innate‐like immunity functions upon recognition of small molecule vitamin B metabolites presented by the MHC, class I‐related protein‐1 (MR1). MAIT cells are profuse in humans, but especially abundant in blood, liver, lungs, and mucosal layers. The mucosa is a common site of carcinogenesis and MAIT cells have been found in both primary and metastatic tumors. MAIT cells target a host of microbes including Mycobacterium tuberculosis, Staphylococcus aureus, Salmonella enterica, Legionella longbeachae, Escherichia coli, and Candida albicans, and are highly activated in viral infections. Cytokines produced by MAIT cells are both anticancerous and antibacterial, but also have proinflammatory and possibly tumorigenic properties. In addition, it is believed that MAIT cells play a protective role in viral infections in an MR1‐independent fashion. Based on our summary of recent advances concerning both MR1‐mediated and MR1‐independent MAIT cell immune responses, we weigh the strengths and weaknesses of these cells for vaccine development.

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

Hofmann

Thimme

2016

Eur J Immunol

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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-...

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Arming of MAIT Cell Cytolytic Antimicrobial Activity Is Induced by IL-7 and Defective in HIV-1 Infection

Cited by 195 publications

References 50 publications

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

Nonreversible MAIT cell‐dysfunction in chronic hepatitis C virus infection despite successful interferon‐free therapy

MAIT cells as attractive vaccine targets

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

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