A divergent transcriptional landscape underpins the development and functional branching of MAIT cells

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing–based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 “mature” MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ–producing MAIT1 cells and interleukin-17–producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)–deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

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Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells

Blood ◽

10.1182/blood-2010-08-303339 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1250-1259 ◽

Cited By ~ 514

Author(s):

Mathilde Dusseaux ◽

Emmanuel Martin ◽

Nacer Serriari ◽

Isabelle Péguillet ◽

Virginie Premel ◽

...

Keyword(s):

T Cells ◽

Antibacterial Properties ◽

Interferon Γ ◽

Receptor Expression ◽

Effector Memory ◽

Interleukin 17 ◽

Ki 67 ◽

Mait Cells ◽

Almost All ◽

Multidrug Resistance Transporter

Abstract Mucosal-associated invariant T (MAIT) cells are very abundant in humans and have antimicrobial specificity, but their functions remain unclear. MAIT cells are CD161hiIL-18Rα+ and either CD4−CD8− (DN) or CD8αβint T cells. We now show that they display an effector-memory phenotype (CD45RA−CD45RO+CD95hiCD62Llo), and their chemokine receptor expression pattern (CCR9intCCR7−CCR5hiCXCR6hiCCR6hi) indicates preferential homing to tissues and particularly the intestine and the liver. MAIT cells can represent up to 45% of the liver lymphocytes. They produce interferon-γ and Granzyme-B as well as high levels of interleukin-17 after phorbol myristate acetate + ionomycin stimulation. Most MAIT cells are noncycling cells (< 1% are Ki-67+) and express the multidrug resistance transporter (ABCB1). As expected from this phenotype, MAIT cells are more resistant to chemotherapy than other T-cell populations. These features might also allow MAIT cells to resist the xenobiotics potentially secreted by the gut bacteria. We also show that this population does not appear to have antiviral specificity and that CD8 MAIT cells include almost all the ABCB1+CD161hi CD8 T cells. Together with their already known abundance and antimicrobial specificity, the gut-liver homing characteristics, high expression of ABCB1, and ability to secrete interleukin-17 probably participate in the antibacterial properties of MAIT cells.

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MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.670531 ◽

2021 ◽

Vol 9 ◽

Author(s):

Tingting Liu ◽

Jie Wang ◽

Kalpana Subedi ◽

Qijun Yi ◽

Li Zhou ◽

...

Keyword(s):

Immune Cell ◽

Cell Lineage ◽

Cell Development ◽

Loss Of Function ◽

Mait Cells ◽

Cellular Processes ◽

Individual Mirnas ◽

Maturation Stages ◽

And Function ◽

Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4–CD8+ subset and decreased CD4–CD8– subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

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Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals

Nature Communications ◽

10.1038/s41467-021-22162-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Huishan Tao ◽

Yun Pan ◽

Shuai Chu ◽

Lei Li ◽

Jinhai Xie ◽

...

Keyword(s):

Cell Expansion ◽

Cell Development ◽

Dependent Manner ◽

Mait Cells ◽

Lineage Differentiation ◽

Ifn Γ ◽

Costimulatory Signals ◽

Β Chain ◽

Cell Effector ◽

Mait Cell

AbstractMucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.

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Type I interferons are important co-stimulatory signals during T cell receptor mediated MAIT cell activation

10.1101/686170 ◽

2019 ◽

Cited By ~ 1

Author(s):

Rajesh Lamichhane ◽

Henry Galvin ◽

Rachel F Hannaway ◽

Sara M de la Harpe ◽

Fran Munro ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Activation ◽

Cell Receptor ◽

Interferon Γ ◽

Type I Interferons ◽

Type I ◽

Mait Cells ◽

Mait Cell

AbstractMucosal associated invariant T (MAIT) cells are abundant unconventional T cells which can be stimulated either via their T cell receptor (TCR) or by innate cytokines. The MAIT cell TCR recognises a pyrimidine ligand, derived from riboflavin synthesising bacteria, bound to MR1. In infection, bacteria not only provide the pyrimidine ligand but also co-stimulatory signals, such as Toll-like receptor agonists, that can modulate TCR-mediated activation. Recently, type I interferons (T1-IFNs) have been identified as contributing to cytokine-mediated MAIT cell activation. However, it is unknown whether T1-IFNs also have a role during TCR-mediated MAIT cell activation. In this study, we investigated the co-stimulatory role of T1-IFNs during TCR-mediated activation of MAIT cells by the MR1 ligand 5-amino-6-D-ribitylaminouracil/methylglyoxal (5-A-RU/MG). We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-A-RU/MG-stimulated MAIT cells. Similarly, influenza virus-induced T1-IFNs enhanced TCR-mediated MAIT cell activation. An essential role of T1-IFNs in regulating MAIT cell activation by riboflavin synthesising bacteria was also demonstrated. The co-stimulatory role of T1-IFNs was confirmed using liver-derived MAIT cells. T1-IFNs acted directly on MAIT cells to enhance their response to TCR stimulation. Overall, our findings establish an important immunomodulatory role of T1-IFNs during TCR-mediated MAIT cell activation.

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MAIT cells regulate NK cell-mediated tumor immunity

Nature Communications ◽

10.1038/s41467-021-25009-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Emma V. Petley ◽

Hui-Fern Koay ◽

Melissa A. Henderson ◽

Kevin Sek ◽

Kirsten L. Todd ◽

...

Keyword(s):

Nk Cells ◽

Tumor Immunity ◽

Nk Cell ◽

Prognostic Significance ◽

Human Tumor ◽

Gene Signature ◽

Mouse Tumor ◽

Mait Cells ◽

Mait Cell

AbstractThe function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.

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