Cigarette smoke components modulate the MR1–MAIT axis

W Awad; JR Mayall; W Xu; MD Johansen; T Patton; XY Lim; I Galvao; LJ Howson; AC Brown; TJ Haw; C Donovan; S Das; GJ Albers; TY Pai; E Hortle; CM Gillis; NG Hansbro; JC Horvat; L Liu; JYW Mak; J McCluskey; DP Fairlie; AJ Corbett; PM Hansbro; J Rossjohn

Journal article

Cigarette smoke components modulate the MR1–MAIT axis

W Awad, JR Mayall, W Xu, MD Johansen, T Patton, XY Lim, I Galvao, LJ Howson, AC Brown, TJ Haw, C Donovan, S Das, GJ Albers, TY Pai, E Hortle, CM Gillis, NG Hansbro, JC Horvat, L Liu, JYW Mak Show all

Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2025

DOI: 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 A9 pocket of MR1. CS inhibited MAIT cell activation, ex vivo, via TCR-dependent and TCR-independent mechanisms. Chronic CS exposure altered ..

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University of Melbourne Researchers

Timothy Patton Author

Lauren J. Howson Author

Gesa Albers Author

McCluskey James Author

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Grants

Awarded by Australian Research Council

Funding Acknowledgements

We acknowledge use of the services and facilities of Monash Macromolecular crystallization facility, Monash FlowCore Platform, and Melbourne Cytometry Platform and thank the staff at the Australian Synchrotron for assistance with data collection. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of Australian Nuclear Science and Technology Organisation, and made use of the Australian Cancer Research Foundation detector. We thank Dr Huy Hoang for his assistance in repeating some of the molecular docking studies. We thank the staff and students who assisted in conducting the murine CS exposure models, Bradley Mitchell, Bre Anderson, Drs. Kurtis Budden, Henry Gomez, Priyanka Sahu, Lohis Balachandran, Sophie Pickles, Saima Firdous Rehman, Vrushali Chimankar, Xiaofan Tu, and Vinod Kumar. This work was supported by program grants from the National Health and Medical Research Council of Australia (NHMRC 1125493, 1113293, and 1138004) and the National Institutes of Health RO1 AI148407-01A1. W. Awad is supported by an Australian ARC Discovery Early Career Researcher Award fellowship (DE220101491). C.M. Gillis is supported by an NHMRC-funded CJ Martin Early Career Fellowship. A.J. Corbett is supported by an Investigator Grant from the NHMRC (1193745) and a Dame Kate Campbell Fellowship from the University of Melbourne. P.M. Hansbro is supported by an Investigator Grant from the NHMRC (1175134), Australian Research Council (ARC), Cancer Council NSW, and University of Technology Sydney. D.P. Fairlie is supported by ARC Center of Excellence (CE200100012). D.P. Fairlie and J. Rossjohn are supported by Investigator Grants from the NHMRC (2009551, 2008981) and J. Rossjohn is supported by an ARC Discovery Project. Open Access funding provided by Cardiff University.