Biology subjects

Hannaway, R. F.

Publications and source records attributed to Hannaway, R. F..

5 recordsLinked to original sources

bioRxiv2025

4-1BB expression and signaling regulates MAIT cell activation and effector functions

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells that recognize microbe-derived riboflavin metabolites presented by MR1. Upon recognition, they become activated, produce proinflammatory cytokines, chemokines and cytotoxic molecules. MAIT cells are also activated by cytokines independently of T cell receptor (TCR) engagement, however these two signals can also act in concert to finetune MAIT cell functions. Additionally, multiple other co-stimulatory signals have also been reported that can boost MAIT cell effector responses to TCR or cytokine stimulation. However, a comprehensive study exploring the role of surface bound TNF receptor superfamily (TNFRSF) molecule 4-1BB, well known for its co-stimulatory function during conventional T cell activation, is lacking in the context of MAIT cells. In this study, we show that 4-1BB is the earliest and most highly expressed TNFRSF co-stimulatory molecule on MAIT cells upon activation by Escherichia coli, with expression seen as early as six hours where it was predominantly MR1 mediated. 4-1BB expression on MAIT cells following late activation was due to both TCR signaling and cytokine signaling. We found marked differences in MAIT cell activation and cytokine expression between 4-1BB+ and 4-1BB- MAIT cells suggesting 4-1BB expression on MAIT cells is associated with functional superiority. By blocking 4-1BB signaling or co-culturing with a 4-1BBL overexpressing cell line we demonstrated an important role of co-stimulation via 4-1BB in MAIT cells during activation. Expression and signaling via 4-1BB also enhanced T-bet and Blimp1 expression. In summary, our study confirms a role for 4-1BB signaling during MAIT cell activation.

immunology↗

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↗

bioRxiv2018

Role of Innate-like Lymphocytes in the Pathogenesis of Community Acquired Pneumonia

BackgroundMucosal-associated invariant T (MAIT) cells and V{delta}2+ {gamma}{delta} T cells are anti-bacterial innate-like lymphocytes (ILLs) that are enriched in blood and mucosa. ILLs have been implicated in control of bacterial infection. However, the role of ILLs in community-acquired pneumonia (CAP) is unknown.\n\nMethodsUsing sputum samples from a well-characterised CAP cohort, MAIT cell (V7.2-J12/20/33) and V{delta}2+ T cell (V{delta}2-J{delta}1/2/3/4) abundance was determined by quantitative PCR. Cytokine and chemokine concentrations in sputum were measured. The capacity of bacteria in sputum to produce activating ligands for MAIT cells and V{delta}2+ T cells was inferred by 16S rRNA sequencing.\n\nResultsMAIT cell abundance in sputum was higher in patients with less severe pneumonia; duration of hospital admission was inversely correlated with both MAIT and V{delta}2+ T cell abundance. The abundance of both ILLs was higher in patients with a confirmed bacterial aetiology, however there was no correlation with total bacterial load or the predicted capacity of bacteria to produce activating ligands. Sputum MAIT cell abundance was associated with interferon- , and interferon-{gamma}, and sputum neutrophil abundance, while V{delta}2+ T cell abundance was associated with CXCL11 and interferon-{gamma}.\n\nConclusionsPulmonary MAIT and V{delta}2+ T cells can be detected in sputum in CAP, where they may contribute to improved clinical outcome.

immunology↗