Rapid glycolytic metabolism underpins mucosal-associated invariant T cell functional responses to innate cytokines
Abstract
Abstract Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that recognizes bacterial-derived antigens presented on MR1. Upon TCR triggering, MAIT cells respond rapidly, producing a range of effector molecules which facilitate host-protective responses in the context of microbial infections. In contrast, MAIT cell responses to viral infection are instead triggered by the recognition of cytokines, and occur independently of TCR engagement. The molecular and metabolic regulation of MAIT cell TCR responses is rapidly emerging, but there is a paucity of data on cytokine driven responses. Here, using high-resolution, quantitative proteomic analysis, we map the downstream proteome of innate cytokine (IL-18/IFNα)–activated MAIT cells, highlighting robust cytokine-driven remodeling and a signature that is distinct from the TCR-driven response. MAIT cells significantly increase protein biosynthesis in response to innate cytokine stimulation and rapidly upregulate the production of IFNγ, granzyme B, and IFN-stimulated gene 15. We demonstrate the metabolic kinetics of MAIT cell responses to cytokine stimulation and highlight a rapid but transient glycolytic burst that is uncoupled from mitochondrial remodeling and contrasts the robust metabolic profile elicited downstream of TCR engagement. Finally, we demonstrate differential contributions from both glycogen and glucose in supporting MAIT cell responses to innate cytokines and further highlight the importance of nutrient availability as a governing signal for MAIT cell fitness and effector functioning.
Article Details
Journal Info
The Journal of Immunology
American Association of Immunologists
Authors (20)
Eimear K Ryan
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Benjamin J Jenkins
Institute of Life Science, Swansea University Medical School , Swansea,
Ronan Bergin
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Rafael E Salazar
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee , Dundee,
Cian Davis
St Vincent’s University Hospital, University College Dublin , Dublin,
Nidhi Kedia-Mehta
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Ali Amini
Lucy C Garner
Translational Gastroenterology and Liver Unit, Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford , Oxford,
Ciara Flynn
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Sinéad Ryan
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Iain Perry
Institute of Life Science, Swansea University Medical School , Swansea,
Joanne C Masterson
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Helen Heneghan
St Vincent’s University Hospital, University College Dublin , Dublin,
Paul N Moynagh
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,
Kirby N Swatek
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee , Dundee,
Paul Klenerman
Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, United Kingdom
Nicholas Jones
Linda V Sinclair
Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee , Dundee,
Donal O’Shea
St Vincent’s University Hospital, University College Dublin , Dublin,
Andrew E Hogan
Kathleen Lonsdale Institute for Human Health Research, Maynooth University , Maynooth, County Kildare,