TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

Abstract

MAIT cells are an abundant T-cell population enriched in peripheral tissues such as the liver. They are activated both through TCR-dependent andindependent mechanisms. However, the different specific functional responses of MAIT cells to these distinct signals remain elusive. We examined the impact of combinations of TCR-dependent and -independent signals in blood and tissue-derived human MAIT cells. TCR-independent activation of MAIT cells from blood and gut was maximised by extending the panel of cytokines to including TNF-superfamily member TL1A. RNAseq experiments revealed that TCR-dependent and -independent signals drive MAIT cells to exert overlapping and unique effector functions, impacting both host defence and tissue homeostasis. While TCR-triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells did show specific enrichment of tissue-repair functions at the level of gene expression, protein production and in in vitro assays and these functions were amplified by cytokine costimulation. Taken together, these data indicate the blend of TCR-dependent and -independent signalling to MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.

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

“…This response was more prominent with TCR activation compared to cytokine activation. Our finding was consistent with those of Leng et al, 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 (Leng et al, 2018), and Hinks et al, who reported enrichment of the tissue repair pathway in 5-OP-RU-stimulated human MAIT cells and MAIT cells from mice acutely infected with L. longbeachae (Hinks et al, 2018); this confirms that the tissue repair function is a unique signature of TCR activated MAIT cells. Therefore, it is now becoming clear that MAIT cells are not just inflammatory and cytolytic T cells but are also helper cells involved in tissue repair and maintaining homeostasis at the mucosal barrier and in the liver.…”

“…Transcriptomic signatures associated with TCR triggering could also be identified. A novel tissue repair signature proposed to be associated with TCR triggering of MAIT cells (Leng et al, 2018) was enriched in MAIT cells following E. coli or 5-A-RU stimulation but not with IL-12+IL-18 (S. Figure 2C).…”

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

“…In summary, the MAIT cell response to TCR stimulation is restricted and a co-stimulatory signal, such as that provided by T1-IFNs, is essential for full activation. While commensal bacteria may act as a source of MAIT cell TCR ligands, partially activating tissue resident MAIT cells (Leng et al, 2018; Sobkowiak et al, 2019; Tang et al, 2013), pro-inflammatory signals, including T1-IFNs, produced during infection/inflammation may synergise with the TCR signal and tune the overall MAIT cell effector response (Figure 8).…”

“…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).…”

“…Since, robust activation can be achieved by both pathogenic and commensal bacteria (Salerno-Goncalves, Rezwan, & Sztein, 2014; Tastan et al, 2018), MAIT cell activation should be tightly controlled to prevent the hyperactivation by commensals and subsequent tissue damage. Indeed, a pure TCR-mediated activation of MAIT cells has been shown to be insufficient to drive sustained activation, with the requirement for additional innate signals (Leng et al, 2018; Slichter et al, 2016; Tang et al, 2013; Turtle et al, 2011). Some recognised innate signals that can modulate activation of MAIT cells via their TCR are IL-7 (Leeansyah et al, 2015; Tang et al, 2013), Toll-like receptor (TLR) agonists (Chen et al, 2017; Ussher et al, 2016), TNFα (Banki et al, 2019), and IL-1β+IL-23 (Tang et al, 2013).…”