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

Abstract

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.

MAIT Cells Display a Specific Response to Type 1 IFN Underlying the Adjuvant Effect of TLR7/8 Ligands

“…How pathogen-derived signals activate protective antimicrobial functions in MAIT cells remains incompletely solved. We provide here strong evidences that IFNα2b (and most likely other type 1 IFN) are important actors in this process, confirming a very recent report (64). We also provide compelling evidences that IFNα induce a specific signaling and transcriptional program in MAIT cells, which could be harnessed for future intervention.…”

Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries

“…MAIT cells have been described as “innate-like” rapid responders, with a memory-like phenotype. However, like conventional T cells, MR1-antigen alone is insufficient to drive an optimal MAIT cell response, with co-stimuli including cytokines and/or surface co-receptors required ( 67 ) and able to enhance MAIT responses to antigen stimulation ( 96 – 99 ), although in vitro findings have not always translated to in vivo studies ( 70 ). Additionally, polarizing effects on MAIT cell function have been demonstrated.…”

MAIT cell activation and dynamics associated with COVID-19 disease severity

“…MAIT cells are activated by T cell receptor (TCR) recognition of microbial vitamin B 2 (riboflavin) metabolites from a range of microbes presented by MHC-Ib-related protein 1 (MR1) molecules (13). However, some MAIT cell functions can be activated or coactivated by cytokines such as interleukin-18 (IL-18) and type I interferons (IFNs) (14,15). MAIT cells rapidly produce IFN-, tumor necrosis factor- (TNF-), and IL-17 and mediate effective cytolytic function dependent on granzyme B (GrzB) (16)(17)(18).…”