Biology subjects

Vernall, A. J.

Publications and source records attributed to Vernall, A. J..

3 recordsLinked to original sources

bioRxiv2019

Neutrophils Suppress Mucosal-Associated Invariant T Cells

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that are abundant in mucosal tissues and the liver where they can respond rapidly to a broad range of riboflavin producing bacterial and fungal pathogens. Neutrophils, which are recruited early to sites of infection, play a non-redundant role in pathogen clearance and are crucial for controlling infection. The interaction of these two cell types is poorly studied. Here, we investigated both the effect of neutrophils on MAIT cell activation and the effect of activated MAIT cells on neutrophils. We show that neutrophils suppress the activation of MAIT cells by a cell-contact and H2O2 dependent mechanism. Moreover, highly activated MAIT cells were able to produce high levels of TNF that induced neutrophil death. We therefore provide evidence for a negative regulatory feedback mechanism in which neutrophils prevent over-activation of MAIT cells and, in turn, MAIT cells limit neutrophil survival.

immunology↗

bioRxiv2019

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

Mucosal 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-{gamma} 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.

immunology↗

bioRxiv2019

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

MAIT cells are an abundant innate-like T cell population which can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidine antigens derived from microbial riboflavin biosynthesis, or via cytokines, such as IL-12 and IL-18. In vivo, these two modes of activation may act in concert or independently depending upon the nature of the microbial or inflammatory stimuli. It is unknown, however, how the MAIT cell response differs to the different modes of activation. Here, we define the transcriptional and effector responses of human MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation through the production of multiple effector cytokines and chemokines, alteration of their cytotoxic granule content and transcription factor expression, and upregulation of co-stimulatory proteins CD40L and 4-1BB. In contrast, cytokine-mediated activation is slower and results in more limited production of cytokines, chemokines, and co-stimulatory proteins; differences in granule content and transcription factor expression are also evident. Therefore, we propose that in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating the immune response, while in the absence of TCR stimulation (e.g. viral infection) their role is likely to differ.

immunology↗