TLR signaling in human antigen‐presenting cells regulates MR1‐dependent activation of MAIT cells

Ussher, James E.; Wilgenburg, Bonnie van; Hannaway, Rachel F.; Ruustal, Kerstin; Phalora, Prabhjeet; Kurioka, Ayako; Hansen, Ted H.; Willberg, Christian; Phillips, Rodney E.; Klenerman, Paul

doi:10.1002/eji.201545969

Cited by 106 publications

(164 citation statements)

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“…It has recently been shown that MR1-mediated MAIT cell activation is tightly regulated and dependent on the integration of innate signals by antigen presenting cells 40 . These innate signals may be altered in HCV infected patients as compared to uninfected controls, and may result in the differential MAIT cell response to E. coli and IL-12/IL-18 stimulation.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…In addition, high expression of receptors for IL-18 and IL-12 (9,31,32) provides MAIT cells with the capacity to respond to antigen-presenting cell (APC)-derived cytokines, recently shown to be important for TCR-mediated activation (33,34), as well as to MR1-independent innate responses (35,36). Given that the activating antigens identified thus far are of bacterial or fungal origin, MR1-independent responses are probably important for the involvement of MAIT cells in viral immunopathogenesis in diseases caused by HIV, HCV, dengue virus, and influenza virus (37)(38)(39)(40).…”

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confidence: 99%

Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines

Dias

Leeansyah

Sandberg

2017

Proc. Natl. Acad. Sci. U.S.A.

191

244

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Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Vα7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity, and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR β-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84, and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin, and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner.

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“…Next, we investigated the cytokine production capacity of MAIT cells by stimulating them specifically via the MR1 receptor using APCs loaded with E. coli , as previously described 16,29 . The stimulation of MAIT cells with E. coli resulted in a much more rapid loss of CD8 expression by MAIT cells than was seen in CD3+ T cells stimulated with E.coli ‐loaded APCs or PMA/ionomycin (Figure S7), which has been demonstrated before 43 .…”

Section: Resultsmentioning

confidence: 74%

“…The stimulation of MAIT cells was adapted and optimized for the use of tetramers for the detection of MAIT cells from previous protocols 16,29 . In short, THP‐1 cells were used as antigen‐presenting cells (APCs).…”

Section: Methodsmentioning

confidence: 99%

645. Mucosal-Associated Invariant T cells in Renal Tissue From Patients With Recurrent Urinary Tract Infections

Terpstra

Sinnige

Remmerswaal

et al. 2018

Open Forum Infectious Diseases

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BackgroundMucosal associated invariant T (MAIT) cells are innate-like T-cells involved in the antibacterial and fungal response by recognizing riboflavin metabolites produced by these organisms. MAIT cells are present in blood and are highly abundant in the mucosa of the liver, lungs and intestines. In murine models of urinary tract infection (UTI), MAIT cells appear to migrate to the bladder and decrease the bacterial load. It is however unknown whether MAIT cells reside in the human urogenital tract and renal tissue and whether they play a role in the first-line defense against (recurrent) UTI (RUTI).MethodsWe used a fluorescently labelled MR1-tetramer in conjunction with 14-color flowcytometry to identify and characterize MAIT cells in renal allografts after allograft failure caused by RUTI (n = 6) or rejection (n = 6) and in healthy kidney tissue surgically removed because of renal cell carcinoma (adjacent nontumorous tissue) (n = 5).ResultsThe mean percentage of MAIT cells within the lymphogate was higher in the RUTI kidneys (2.24%) compared with the rejection kidneys (0.14%) and the control kidneys (0.11%) (P < 0.05).Characterization of MAIT cells was impossible in some control samples due to MAIT cells counts <25 (predefined cutoff value), therefore the control group was excluded from further statistical analysis.MAIT cells in RUTI kidneys appear to have a less activated profile compared with the rejection kidneys, with a lower expression of Ki67 (P < 0.01). Though the expression of the tissue resident marker CD69/CD103 was higher in 4/6 RUTI kidneys, this difference was not significant.ConclusionMAIT cells are present in renal tissue that is or has been subjected to an immunologic response. MAIT cells in RUTI kidneys display a more quiescent and in some samples more tissue resident phenotype than MAIT cells in rejection kidneys. These findings may suggest that (I) MAIT cells play a role in the first-line defense in the kidney and (II) that after RUTI, MAIT cells remain in renal tissue in a quiescent state. We postulate that this might be favorable in case of a second hit from an uropathogen.Figure 1.Presence and characterization of MAIT cells in renal tissue.Disclosures F. Bemelman, Astellas: We received an unrestricted grant from Astellas to establish a Biobank for patients with renal diseases. The samples described in this abstract are obtained from this Biobank., Grant recipient.

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TLR signaling in human antigen‐presenting cells regulates MR1‐dependent activation of MAIT cells

Cited by 106 publications

References 42 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

Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines

645. Mucosal-Associated Invariant T cells in Renal Tissue From Patients With Recurrent Urinary Tract Infections

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