Cigarette smoke components modulate the MR1-MAIT axis

Awad, Wael, Mayall, Jemma R., Xu, Weijun, Johansen, Matt D., Patton, Timothy, Lim, Xin Yi, Galvao, Izabela, Howson, Lauren J., Brown, Alexandra C., Haw, Tatt Jhong, Donovan, Chantal, Das, Shatarupa, Albers, Gesa J., Pai, Tsung-Yu, Hortle, Elinor, Gillis, Caitlin M., Hansbro, Nicole G., Horvat, Jay C., Liu, Ligong, Mak, Jeffrey Y. W., McCluskey, James, Fairlie, David P., Corbett, Alexandra J., Hansbro, Philip M. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2025. Cigarette smoke components modulate the MR1-MAIT axis. Journal of Experimental Medicine 222 (2) , e20240896. 10.1084/jem.20240896

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Abstract

Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs. Using in silico, cellular, and biochemical approaches, we identified components of CS that bind MR1 and impact MR1 cell surface expression. Compounds, including nicotinaldehyde, phenylpropanoid, and benzaldehyde-related scaffolds, bound within the A' pocket of MR1. CS inhibited MAIT cell activation, ex vivo, via TCR-dependent and TCR-independent mechanisms. Chronic CS exposure altered MAIT cell phenotype and function and attenuated MAIT cell responses to influenza A virus infection in vivo. MR1-deficient mice were partially protected from the development of chronic obstructive pulmonary disease (COPD) features that were associated with CS exposure. Thus, CS can impair MAIT cell function by diverse mechanisms, and potentially contribute to infection susceptibility and disease exacerbations.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: Title: cc by, Type: cc by
Publisher:	Rockefeller University Press
ISSN:	0022-1007
Date of First Compliant Deposit:	27 January 2025
Date of Acceptance:	27 November 2024
Last Modified:	27 Jan 2025 18:30
URI:	https://orca.cardiff.ac.uk/id/eprint/175652

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