Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

Lamichhane, Rajesh; Schneider, Marion; Harpe, Sara M. de la; Harrop, Thomas W. R.; Hannaway, Rachel F.; Dearden, Peter K.; Kirman, Joanna R.; Tyndall, Joel D. A.; Vernall, Andrea J.; Ussher, James E.

doi:10.1101/600189

Cited by 6 publications

(19 citation statements)

References 69 publications

(108 reference statements)

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“…Intriguingly, at this early time point, perforin expression appears to be completely dependent on T1-IFNs. This is consistent with two previous studies that show TCR-independent perforin production by MAIT cells activated by E. coli for 6 and 24 hours (Kurioka et al, 2015; Lamichhane et al, 2019).…”

Section: Discussionsupporting

confidence: 94%

“…Bacteria can provide both MR1 ligand and co-stimulatory signals leading to robust activation of MAIT cells (Chen et al, 2017; Ussher et al, 2016). Recently, we reported that various innate signalling pathways, including IFNα/β signalling, were enriched early in MAIT cells upon stimulation with E. coli compared to activation with 5-A-RU alone (Lamichhane et al, 2019). Therefore, we activated MAIT cells with E. coli for 6 hours with or without B18R to assess the role of T1-IFNs during early MAIT cell activation by a riboflavin synthesising bacteria.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, in a mouse model, co-administration of TLR agonists was required for accumulation of MAIT cells in the lung in response to intra-nasal 5-OP-RU (Chen et al, 2017; Ussher et al, 2016). Interestingly, we recently reported that T1-IFN signalling pathways are upregulated early in MAIT cells activated by E. coli , but not by 5-A-RU (Lamichhane et al, 2019). In this study, we demonstrated that T1-IFNs are important early co-stimulatory signals during activation by E. coli .…”

Section: Discussionmentioning

confidence: 99%

“…MR1 ligand 5-amino-6-D-ribitylaminouracil (5-A-RU) was synthesised as previously reported (Lamichhane et al, 2019). 5-A-RU were stored as single use aliquots at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Upon activation, MAIT cells produce pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα), interferon gamma (IFNγ), and IL-17A, as well as cytotoxic molecules (granzymes and perforin) (Billerbeck et al, 2010; Dusseaux et al, 2011; Kurioka et al, 2015; Le Bourhis et al, 2013). The exact effector functions expressed depend upon the mode of activation (Hinks et al, 2018; Lamichhane et al, 2019; Leng et al, 2018). Many in vivo studies have established an important role for MAIT cells in protection against bacterial infections (Chua et al, 2012; Georgel, Radosavljevic, Macquin, & Bahram, 2011; Meierovics, Yankelevich, & Cowley, 2013; Wang et al, 2018) and more recently against viruses (Wilgenburg et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Lamichhane

Galvin

Hannaway

et al. 2019

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Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells that can be stimulated either via their 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 TLR 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. We found that T1‐IFNs were able to boost interferon‐γ and granzyme B production in 5‐amino‐6‐d‐ribitylaminouracil/methylglyoxal‐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 also evident in 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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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…MR1 ligand 5-amino-6-D-ribitylaminouracil (5-A-RU) was synthesised as previously reported (Lamichhane et al, 2019). 5-A-RU were stored as single use aliquots at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lamichhane

Galvin

Hannaway

et al. 2019

Preprint

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

et al. 2019

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Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells thatcan be stimulated either via their 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 TLR 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 TCRmediated 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-Dribitylaminouracil/methylglyoxal. We found that T1-IFNs were able to boost interferon-γ and granzyme B production in 5-amino-6-D-ribitylaminouracil/methylglyoxal-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 also evident in 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.Keywords: co-stimulation r influenza virus r mucosal associated invariant T cells r TCR activation r type I interferons Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

Tourret

Talvard-Balland

Lambert

et al. 2021

Preprint

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BackgroundMucosal associated invariant T (MAIT) cells are semi-invariant T cells that recognize microbial antigens presented by the highly conserved MR1 molecule. MAIT cells are predominantly localized in the liver and barrier tissues and are potent effectors of anti - microbial defense. MAIT cells are very few at birth and accumulate gradually over a period of about 6 years during infancy. The cytotoxic potential of MAIT cells, as well as their newly described regulatory and tissue repair functions, open the possibility of exploiting their properties in adoptive therapy. A prerequisite for their use as “universal” cells would be a lack of alloreactive potential, which remains to be demonstrated.MethodsWe used ex vivo, in vitro and in vivo models to determine if human MAIT cells contribute to allogeneic responses.ResultsWe show that recovery of MAIT cells after allogeneic hematopoietic stem cell transplantation recapitulates their slow physiological expansion in early childhood, independent of recovery of conventional T cells. In vitro, signals provided by allogeneic cells and cytokines do not induce sustained MAIT cell proliferation. In vivo, human MAIT cells do not expand nor accumulate in tissues in a model of T-cell mediated xenogeneic graft-versus-host disease (GVHD) in immunodeficient mice.ConclusionsAltogether, these results provide evidence that MAIT cells are devoid of alloreactive potential and pave the way for harnessing their translational potential in universal adoptive therapy overcoming barriers of HLA disparity.

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Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

Cited by 6 publications

References 69 publications

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

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

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

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

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