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Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells.

ABSTRACT: Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCR?7.2^- conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCR?7.2 segment associated with J?33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCR?7.2⁺ CD161^- T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCR?7.2^- conventional T cells and TCR?7.2⁺ CD161^- T cells. Genome-wide transcriptomes of MAIT cells, TCR?7.2^- conventional T cells, and TCR?7.2⁺ CD161^- T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCR?7.2^- conventional T cells and TCR?7.2⁺ CD161^- T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCR?7.2^- conventional T cells and TCR?7.2⁺ CD161^- T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.

SUBMITTER: Park D

PROVIDER: S-EPMC6506535 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells.

Park Daeui D Kim Hong Gi HG Kim Miok M Park Tamina T Ha Hyung-Ho HH Lee Dae Ho DH Park Kang-Seo KS Park Seong Jun SJ Lim Hwan Jung HJ Lee Chang Hoon CH

Scientific reports 20190508 1

Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2<sup>-</sup> conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2<sup>+</su ...[more]

PMID: 31068647

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Project description:Over the past decade, we have contributed to the chemistry of microbial natural products and synthetic ligands, related to riboflavin and uracils, that modulate immune cells called mucosal associated invariant T cells (MAIT cells). These highly abundant T lymphocytes were only discovered in 2003 and have become recognized for their importance in mammalian immunology. Unlike other T cells, MAIT cells are not activated by peptide or lipid antigens. In collaboration with immunology and structural biology research groups, we discovered that they are instead activated by unstable nitrogen-containing heterocycles synthesized by bacteria. The most potent naturally occurring activating compound (antigen) is 5-(2-oxopropylideneamino)-d-ribitylaminouracil (5-OP-RU). This compound is an imine (Schiff base) formed through condensation between an intermediate in the biosynthesis of riboflavin (vitamin B2) and a metabolic byproduct of mammalian and microbial glycolysis. Although it is very unstable in water due to intramolecular ring closure or hydrolysis, we were able to develop a non-enzymatic synthesis that yields a pure kinetically stable compound in a nonaqueous solvent. This compound has revolutionized the study of MAIT cell immunology due to its potent activation (EC50 = 2 pM) of MAIT cells and its development into immunological reagents for detecting and characterizing MAIT cells in tissues. MAIT cells are now linked to key physiological processes and disease, including antibacterial defense, tissue repair, regulation of graft-vs-host disease, gastritis, inflammatory bowel diseases, and cancer. 5-OP-RU activates MAIT cells and, like a vaccine, has been shown to protect mice from bacterial infections and cancers. Mechanistic studies on the binding of 5-OP-RU to its dual protein targets, the major histocompatibility complex class I related protein (MR1) and the MAIT cell receptor (MAIT TCR), have involved synthetic chemistry, 2D 1H NMR spectroscopy, mass spectrometry, computer modeling and molecular dynamics simulations, biochemical, cellular, and immunological assays, and protein structural biology. These combined studies have revealed structural influences for 5-OP-RU in solution on protein binding and antigen presentation and potency; informed the development of potent (EC50 = 2 nM) and water stable analogues; led to fluorescent analogues for detecting and tracking binding proteins in and on cells; and enabled discovery of drugs and drug-like molecules that bind MR1 and modulate MAIT cell function. MAIT cells offer new opportunities for chemical synthesis to enhance the stability, potency, selectivity, and bioavailability of small molecule ligands for MR1 or MAIT TCR proteins, and to contribute to the understanding of T cell immunity and the development of prospective new immunomodulating medicines.

Project description:Introduction Mucosal Associated Invariant T (MAIT) cells are innate-like T cells that respond to conserved pathogen-derived vitamin B metabolites presented by the MHC class I related-1 molecule (MR1) antigen presentation pathway. Whilst viruses do not synthesize these metabolites, we have reported that varicella zoster virus (VZV) profoundly suppresses MR1 expression, implicating this virus in manipulation of the MR1:MAIT cell axis. During primary infection, the lymphotropism of VZV is likely to be instrumental in hematogenous dissemination of virus to gain access to cutaneous sites where it clinically manifests as varicella (chickenpox). However, MAIT cells, which are found in the blood and at mucosal and other organ sites, have yet to be examined in the context of VZV infection. The goal of this study was to examine any direct impact of VZV on MAIT cells. Methods Using flow cytometry, we interrogated whether primary blood derived MAIT cells are permissive to infection by VZV whilst further analysing differential levels of infection between various MAIT cell subpopulations. Changes in cell surface extravasation, skin homing, activation and proliferation markers after VZV infection of MAIT cells was also assessed via flow cytometry. Finally the capacity of MAIT cells to transfer infectious virus was tested through an infectious center assay and imaged via fluorescence microscopy. Results We identify primary blood-derived MAIT cells as being permissive to VZV infection. A consequence of VZV infection of MAIT cells was their capacity to transfer infectious virus to other permissive cells, consistent with MAIT cells supporting productive infection. When subgrouping MAIT cells by their co- expression of a variety cell surface markers, there was a higher proportion of VZV infected MAIT cells co-expressing CD4+ and CD4+/CD8+ MAIT cells compared to the more phenotypically dominant CD8+ MAIT cells, whereas infection was not associated with differences in co-expression of CD56 (MAIT cell subset with enhanced responsiveness to innate cytokine stimulation), CD27 (co-stimulatory) or PD-1 (immune checkpoint). Infected MAIT cells retained high expression of CCR2, CCR5, CCR6, CLA and CCR4, indicating a potentially intact capacity for transendothelial migration, extravasation and trafficking to skin sites. Infected MAIT cells also displayed increased expression of CD69 (early activation) and CD71 (proliferation) markers. Discussion These data identify MAIT cells as being permissive to VZV infection and identify impacts of such infection on co- expressed functional markers.

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Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells.

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Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells.

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