TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

Leng, Tianqi; Akther, Hossain Delowar; Hackstein, Carl-Philipp; Powell, Kate; King, T. P.; Friedrich, Matthias; Christoforidou, Z; McCuaig, Sarah; Neyazi, Mastura; Arancibia‐Cárcamo, Carolina V.; Hagel, Joachim; Powrie, Fiona; Peres, Raphael Sanches; Millar, Val; Ebner, Daniel; Lamichhane, Rajesh; Ussher, James E.; Hinks, Tsc; Marchi, Emanuele; Willberg, C; Klenerman, Paul

doi:10.1016/j.celrep.2019.08.050

Cited by 208 publications

(295 citation statements)

References 62 publications

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“…This response was evident with TCR activation but not with cytokine activation. Our finding was consistent with those of Leng et al (2019), who demonstrated a similar enrichment of genes involved in tissue repair functions in TCR and TCR+cytokine but not cytokine triggered peripheral human MAIT cells, and Hinks et al (2019), who reported an enrichment of the tissue repair pathway in 5-OP-RU-stimulated human MAIT cells and MAIT cells from mice acutely infected with L. longbeachae. Together, this confirms that the tissue repair function is a signature of TCR-activated MAIT cells.…”

Section: Discussionsupporting

confidence: 92%

“…Transcriptomic signatures associated with TCR triggering could also be identified. A tissue repair signature proposed to be associated with TCR triggering of MAIT cells (Leng et al, 2019;Hinks et al, 2019) was enriched in MAIT cells following E. coli or 5-A-RU stimulation but not with IL-12+IL-18 ( Figure S2C).…”

Section: Distinct Transcriptional Profiles Of Tcr-and Cytokine-stimulmentioning

confidence: 98%

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TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses

et al. 2019

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Graphical AbstractHighlights d RNA sequencing of MAIT cells following stimulation via T cell receptor or cytokines d TCR and cytokines induce distinct transcriptome with different modes of activation d TCR stimuli result in a rapid, polyfunctional, proinflammatory response d Cytokine stimulation results in a slower, more restricted response SUMMARY Mucosal-associated invariant T (MAIT) cells can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidines derived from microbial riboflavin biosynthesis, or via cytokines. These two modes of activation may act in concert or independently, depending upon the stimulus. It is unknown, however, how MAIT cell responses differ with the mode of activation. Here, we define transcriptional and effector responses of human CD8 + MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation, producing multiple cytokines and chemokines, altering their cytotoxic granule content and transcription factor expression, and upregulating co-stimulatory proteins. In contrast, cytokine-mediated activation is slower and results in a more limited response. Therefore, we propose that, in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating immune responses, while in the absence of TCR stimulation, their role is likely to differ.

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Section: Discussionsupporting

confidence: 92%

Section: Distinct Transcriptional Profiles Of Tcr-and Cytokine-stimulmentioning

confidence: 98%

TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses

et al. 2019

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“…Similarly to H2-M3 restricted CD8 + T cells, in this position MAIT cells are poised to maintain tissue homeostasis in the presence of commensals thereby limiting inflammation and associated tissue injury 32 . These data are consistent with a similar finding of this same tissue repair signature observed by GSEA analysis of MAIT cells when activated by TCR triggering, but not observed in the context of cytokine-mediated activation 33 . These findings might also explain the increased gut permeability observed in Mr1 -/- NOD mice compared with Mr1 +/- NOD littermates, which suggested a protective role for MAIT cells for maintaining gut homeostasis 34 .…”

Section: Discussionsupporting

confidence: 92%

Activation and in vivo evolution of the MAIT cell transcriptome in mice and humans reveals diverse functionality

Hinks

Marchi

Jabeen

et al. 2018

Preprint

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22Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells 23 conserved across mammalian species, including mice and humans. By sequencing RNA 24 from sorted MR1-5-OP-RU tetramer + cells derived from either human blood or murine 25 lungs, we define the basic transcriptome of an activated MAIT cell in both species and 26 demonstrate how this profile changes during resolution and reinfection phases of infection. 27We observe strong similarities between MAIT cells in humans and mice. Compared with 28 previously published T cell transcriptomes, MAIT cells displayed most similarity to iNKT 29 cells when activated, but to gd T cells, after resolution of infection. In both species 30 activation leads to strong expression of pro-inflammatory cytokines and chemokines, and 31 also a strong tissue repair signature, recently described in murine commensal-specific H2-32 M3-restricted T cells. These data define the requirements for, and consequences of, MAIT 33 cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in 34 both species. 35 36 Key words 37 Mucosal-associated invariant T cell, T cell, transcriptome, MHC-related protein 1, 38 activation, lung, human, mouse, riboflavin. 39 40 3 Mucosal-associated invariant T (MAIT) cells are innate-like T cells which express a 'semi-41 invariant' ab T cell receptor (TCR) and recognise metabolic derivatives of riboflavin 42 biosynthesis 1-3 presented on the restriction molecule major histocompatibility complex 43 (MHC)-related protein-1 (MR1) 4,5 . These antigens, which include the potent MAIT cell 44 ligand 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) 6 , are produced by a 45 wide variety of bacteria, mycobacteria and yeasts 1,7 , but are absent from mammals, and 46 therefore allows host -pathogen discrimination. MAIT cells have a strong pro-47 Our data reveal strong similarities between MAIT cells in humans and in mice at a 64 transcriptional level, show that MAIT cells displayed the closest similarities to invariant 65 natural killer T (iNKT) cells when activated, but after resolution of infection were more 66 comparable to gd T cells, and reveal a previously unknown tissue repair phenotype 67 expressed upon MAIT cell activation in both species. 68 69 Results 70 Activation requirements of MAIT cells in vivo 71First we aimed to test, systematically, the activation requirements of MAIT cells in vivo in 72 mouse lungs. We have previously shown that pulmonary MAIT cell frequencies in mice 73 can be markedly enhanced by intranasal administration of 5-OP-RU if it is co-administered 74 with S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys), CpG ODN 1668 or 75 polyinosinic:polycytidylic acid (poly I:C), which are agonists for TLR2/6, TLR9 and 76 TLR3, respectively. We therefore investigated agonists for each of the murine TLRs, using 77 the maximum doses presented in a literature review of previous studies of these 78 compounds. All animals received the relevant TLR intranasally on day 0. In experimental 79 animals...

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“…Although there are currently no reports of tumor antigens presented by MR1 to MAIT cells (13)(14)(15)(16), MAIT cells upregulate granzyme B and perforin following activation (5,17,18) and have the capacity to kill tumor cells pulsed with the MAIT cell antigen 5-(2oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) (19), suggesting that MAIT cells are capable of eliciting direct anti-tumor immune responses. Furthermore, MAIT cells can be activated by inflammatory cytokines, such as IL-12, IL-18 and TL1A (20,21), and express receptors known to activate NK cells following interaction with their respective ligands expressed on tumor cells, including DNAM-1 and NKG2D (22,23). These observations suggest that MAIT cells may be activated within the tumor microenvironment (TME) through alternative mechanisms to direct recognition of tumor antigens and have the potential to detect tumor cells other than through presentation of antigens by MR1.…”

Section: Introductionmentioning

confidence: 99%

MAIT cells regulate NK cell mediated tumor immunity

Petley

Koay

Henderson

et al. 2020

Preprint

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MR1-restricted mucosal-associated invariant T (MAIT) cells recognize microbial metabolites and play an important role in immunity to infection, however, the role they play in tumor immunity is unclear. Here we show that MAIT cell-deficient mice are more resistant to subcutaneous and lung metastasis B16F10 tumor growth compared to control mice, an effect that was associated with enhanced NK cell numbers and was NK cell-dependent. Analysis of this interplay in cancer patients also revealed that a high expression of a novel MAIT gene signature negatively impacted the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or antigen-mediated MAIT cell activation in vivo, enhanced immunity against B16F10 and E0771 lung tumor metastasis. Furthermore, MAIT cell activation effectively reduced metastatic burden in a more stringent model of established lung metastases in mice. These effects were associated with enhanced NK cell responses and increased expression of both IFNγ-dependent and inflammatory genes in NK cells, which was neutralized by IFNγ blockade. Importantly, activated human MAIT cells also enhanced the function of NK cells isolated from patient tumor samples. These findings provide insight into the contrasting roles that MAIT cells can play in controlling anti-tumor immune responses depending on their activation status, in both mice and humans, and suggest potential therapeutic avenues for exploiting their potential anti-tumor properties for cancer treatment.

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TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

Cited by 208 publications

References 62 publications

TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses

TCR- or Cytokine-Activated CD8+ Mucosal-Associated Invariant T Cells Are Rapid Polyfunctional Effectors That Can Coordinate Immune Responses

Activation and in vivo evolution of the MAIT cell transcriptome in mice and humans reveals diverse functionality

MAIT cells regulate NK cell mediated tumor immunity

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