Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Abstract

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFNγ (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

MAITabolism2 – the emerging understanding of MAIT cell metabolism and their role in metabolic disease

“…In conventional T cells, mitochondrial ROS (mROS) has been linked to elevated IL-17 ( 48 ), and we demonstrated that reducing mROS levels in obese MAIT cells limited IL-17 production, linking IL-17 to mitochondrial metabolism. In a recent pre-print from the Kronenberg lab, single cell sequencing of murine MAIT cells subsets revealed elevated uptake of fatty acids, lipid content, and mitochondrial potential in IL-17 producing MAIT cells when compared to IFNγ producing MAIT cell subsets ( 49 ).…”

Unraveling the Phenotypic States of Human innate-like T Cells: Comparative Insights with Conventional T Cells and Mouse Models

“…This differs from the predominant effector association of Tinn cells in mouse thymus, where distinct effector subsets that closely resemble CD4 T helper cells and innate lymphoid cells develop and reside (Krovi et al, 2022;Lee et al, 2020;Legoux et al, 2019). To explore the similarities in the transcriptional signatures of mouse and human Tinn cells, we first constructed a reference mouse Tinn dataset, comprising data from nine different studies (Baranek et al, 2020;Chandra et al, 2023;Harsha Krovi et al, 2020;Koay et al, 2019;Lee et al, 2020;Legoux et al, 2019;Li et al, 2022;Maas-Bauer et al, 2021;Wang et al, 2023). This merged dataset revealed 13 transcriptionally distinct clusters, where iNKT, MAIT, and gd T cells coexisted, with variable proportions (Fig 6A and Supplementary Fig 14, Table XIII).…”

“…While studies in mice have delineated the developmental trajectories of Tinn and analyses of distinct subsets of peripheral human Tinn cells have shed light on the developmental stages of human Vd2-Vg9 (Perriman et al, 2023), and functional subtypes of human MAIT cells (Chandra et al, 2023;Garner et al, 2023), a comprehensive picture spanning development and peripheral function across Tinn and Tconv is lacking. In this study, we utilized the unbiased potential of singlecell genomics combined with flow cytometry to assess the range of phenotypic states Tconv and Tinn cells can adopt in vivo in the human thymus and blood.…”

Comparative transcriptomes reveal pro-survival and cytotoxic programs of mucosal-associated invariant T cells upon Bacillus Calmette–Guérin stimulation

“…The comparative MAIT cell transcriptomes stimulated by mycobacteria versus extracellular bacteria are expected to provide MAIT cell activation features and pathways potentially crucial for fighting mycobacterial infections. Recent MAIT cell transcriptomes, including single-cell transcriptomes, have differentiated various MAIT cell subsets in mice ( Chandra et al., 2021 ; Tao et al., 2021 ) and humans ( Vorkas et al., 2022 ). Moreover, human MAIT cell stimulation through signaling, cytokines, anti-CD3/CD28, or bacterial infections display transcriptomes associated with tissue repair ( Hinks et al., 2019 ; Leng et al., 2019 ; Chandra et al., 2021 ; Tao et al., 2021 ; Vorkas et al., 2022 ), polyfunctional effector functions ( Koay et al., 2019 ; Lamichhane et al., 2019 ; Salou et al., 2019 ; Lee et al., 2020 ), and innate-like activation programs ( Sharma et al., 2020 ).…”

“…Recent MAIT cell transcriptomes, including single-cell transcriptomes, have differentiated various MAIT cell subsets in mice ( Chandra et al., 2021 ; Tao et al., 2021 ) and humans ( Vorkas et al., 2022 ). Moreover, human MAIT cell stimulation through signaling, cytokines, anti-CD3/CD28, or bacterial infections display transcriptomes associated with tissue repair ( Hinks et al., 2019 ; Leng et al., 2019 ; Chandra et al., 2021 ; Tao et al., 2021 ; Vorkas et al., 2022 ), polyfunctional effector functions ( Koay et al., 2019 ; Lamichhane et al., 2019 ; Salou et al., 2019 ; Lee et al., 2020 ), and innate-like activation programs ( Sharma et al., 2020 ). However, MAIT cells stimulated by MR1 antigen presentation with different bacterial infections or stimulations display heterogeneous responses that have been considered as pathogen selectivity, labeled with diverse sequences of TCRβ chain and an invariant α chain, and attributed to potentially different antigens from various bacteria ( Reantragoon et al., 2013 ; Gold et al., 2014 ; Jiang et al., 2014 ; Lepore et al., 2014 ; Sakala et al., 2015 ; Meermeier et al., 2016 ).…”