Alexandra J. Corbett
James E. Ussher
Timothy S. C. Hinks- 1Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia
- 2Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
- 3Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
Editorial on the Research Topic
MAIT cells come of age
Mucosal-associated Invariant T (MAIT) cells recognise microbial metabolite-derived antigens presented by the MHC Class I related (MR1) protein (1, 2). In the decade since MR1-MAIT antigen discovery, the role of MAIT cells in anti-microbial immunity has been well defined, with diverse functions, including maintenance of barrier integrity and tissue repair, being described more recently. MAIT cells can drive pathology in chronic infections and have been associated with poor outcomes in certain autoimmune diseases, cancer, and COVID-19 (3–5). Current research considers the impact of host genetics, interactions of MAIT cells with pathogens, other immune cells, stromal cells, and the microbiome, and looks towards therapeutic targeting of this unconventional immune axis.
Humans with natural immune cell deficiencies provide unique insight into the relevance of cell subsets in health. MAIT cell deficiencies were initially elusive, but as the field has developed and their frequencies are now routinely assessed in clinical immunology, MAIT deficiency and dysfunction has been described in several studies. Howson and Bryant summarise these, allowing common themes to emerge. MAIT cells are reduced in a wide range of inborn errors of immunity that are associated with bacterial, fungal or viral infections. However, as these occur as part of wider immune disruptions, it is hard to attribute causality. Interestingly in rare cases of pure MAIT deficiency, a tendency to viral infections was as prominent a feature as bacterial infections, underlining the importance of both TCR-dependent and TCR-independent functions.
MAIT cell activation during viral infections is mediated via cytokines and independent of MR1 (6). Intriguingly, viral downregulation of MR1 expression, reminiscent of immune evasion mechanisms impacting MHC Class I antigen presentation, has been described (7, 8). Ashley et al. investigate the ability of human cytomegalovirus (HCMV), a betaherpesvirus known to cause immune dysregulation, to dampen MR1-MAIT immunity. They show HCMV can suppress MR1 expression in infected fibroblasts, resulting in the inhibition of MAIT cell activation. As previously reported for MHC Class I, bystander cells increased their expression of MR1. The authors identify HCMV glycoprotein gpUS9 as an immune evasion molecule capable of targeting MR1. Its impact on TCR-dependent MAIT cell activation by concomitant bacterial infections remains to be determined.
Varicella Zoster Virus (VZV) can similarly impact MR1 expression (8). Here, Purohit et al. demonstrate another VZV-MAIT cell interaction; the direct productive infection of MAIT cells by VZV, with infected cells showing higher expression of activation and proliferation markers, and higher frequencies of infection in the CD4-expressing subsets. Their results, including retained expression of migration and skin-homing markers in infected cells, and the ability to transmit virus to other cells, raise the possibility that MAIT cells may act as a Trojan horse, contributing to viral dissemination throughout the host.
MAIT cells can produce IFN-γ following stimulation (9–11), but while they express receptors for and are responsive to type I interferons (6, 12), their role in producing type I interferon is less appreciated. Jakob et al. assessed the MAIT cell translatome, using CLICK chemistry to identify newly synthesized proteins from MAIT cells in response to antigen. Consistent with single-cell transcriptomic data, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) induced MAIT cell production of several type I IFN signalling proteins. The signals driving this response are yet to be determined. This study also showed evidence that MR1-activated MAIT cells could promote M1 macrophage polarisation, highlighting the role MAIT cells may play in influencing monocyte and macrophage phenotype, with potential consequences for immunity during pathogen responses and homeostasis.
While the MR1-MAIT axis is highly conserved, polymorphisms in other immune genes may impact MAIT immunity. MAIT cells have high IL7R expression and IL-7 is important for their homeostasis and activation. MAIT cells are depleted and functionally exhausted in a range of viral infections, including HIV (13–16). As IL-7 correlates with MAIT cell frequencies in HIV infected individuals, Han et al. studied the impact of IL7RA polymorphisms on circulating MAIT cells in healthy individuals and HIV infected individuals after long-term anti-retroviral therapy (ART). While MAIT cell dysfunction in chronic HIV was not associated with IL17RA haplotype, ‘haplotype 2’ was associated with increased MAIT numbers in healthy controls and greater recovery following ART.
While T cell metabolic changes are essential for effector function, MAIT and other innate-like T cells sit outside the norms of naïve, activated and effector definitions as they exit the thymus in an effector-memory-like state (17, 18). Several studies have assessed MAIT cells in the context of metabolic diseases, but the metabolism of MAIT cells themselves is just emerging. Kedia-Mehta and Hogan review current knowledge both on their functions in metabolic disease and how alterations in metabolism impact MAIT immunity.
The MR1-MAIT axis is both stimulated by microbial antigens from the commensal microbiome and contributes to the shaping of the microbiome. As MAIT cells become more widely studied, and as the analytic power of microbial metagenomics increases, we are discovering more about these interactions. A review by Jabeen and Hinks integrates findings and speculates on future therapeutic manipulation of MAIT cells by antigens or microbiota. It will be important to understand the functions of MAIT cells during homeostasis, which may yet prove to be their most influential role.
MAIT cell anti-bacterial protective responses have been demonstrated in mouse studies with bacterial pathogens that cause marked expansion of MAIT cells, while the low frequency of MAIT cells in laboratory mice relative to humans makes their assessment difficult in other settings. Building on previous methods of expanding MAIT cells by the same group (19–21), Nelson et al. demonstrate the utility of the MAIT antigen precursor 5-amino-6-D-ribitylaminouracil (5-A-RU) in expansion and activation protocols to enable further MAIT cell study in mice, and also speculate on 5-A-RU as a common precursor of diverse MAIT antigens.
Overall, this Research Topic points towards a bright future as the field considers therapy informed by the specific functions of MAIT cells and their role in different immune contexts. As MAIT cells come of age, in vivo studies and clinical trials of MAIT cell therapies will be the next frontier for this intriguing T cell subset.
Author contributions
AC: Conceptualization, Writing – original draft, Writing – review & editing. JU: Conceptualization, Writing – original draft, Writing – review & editing. TH: Conceptualization, Writing – original draft, Writing – review & editing.
Conflict of interest
AC is an inventor on patents WO2014/005194 and WO2015/149130 describing MR1 tetramersand MR1 ligands.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Kjer-Nielsen L, Patel O, Corbett AJ, Le Nours J, Meehan B, Liu L, et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature (2012) 491(7426):717–23. doi: 10.1038/nature11605
2. Corbett AJ, Eckle SB, Birkinshaw RW, Liu L, Patel O, Mahony J, et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature (2014) 509(7500):361–5. doi: 10.1038/nature13160
3. Godfrey DI, Koay HF, McCluskey J, Gherardin NA. The biology and functional importance of MAIT cells. Nat Immunol (2019) 20(9):1110–28. doi: 10.1038/s41590-019-0444-8
4. Toubal A, Nel I, Lotersztajn S, Lehuen A. Mucosal-associated invariant T cells and disease. Nat Rev Immunol (2019) 19(10):643–57. doi: 10.1038/s41577-019-0191-y
5. Parrot T, Gorin JB, Ponzetta A, Maleki KT, Kammann T, Emgard J, et al. MAIT cell activation and dynamics associated with COVID-19 disease severity. Sci Immunol (2020) 5(51):eabe1670. doi: 10.1101/2020.08.27.20182550
6. van Wilgenburg B, Scherwitzl I, Hutchinson EC, Leng T, Kurioka A, Kulicke C, et al. MAIT cells are activated during human viral infections. Nat Commun (2016) 7:11653. doi: 10.1038/ncomms11653
7. McSharry BP, Samer C, McWilliam HEG, Ashley CL, Yee MB, Steain M, et al. Virus-mediated suppression of the antigen presentation molecule MR1. Cell Rep (2020) 30(9):2948–62 e4. doi: 10.1016/j.celrep.2020.02.017
8. Purohit SK, Samer C, McWilliam HEG, Traves R, Steain M, McSharry BP, et al. Varicella zoster virus impairs expression of the nonclassical major histocompatibility complex class I-related gene protein (MR1). J Infect Dis (2023) 227(3):391–401. doi: 10.1093/infdis/jiab526
9. Hinks TSC, Marchi E, Jabeen M, Olshansky M, Kurioka A, Pediongco TJ, et al. Activation and in vivo evolution of the MAIT cell transcriptome in mice and humans reveals tissue repair functionality. Cell Rep (2019) 28(12):3249–62 e5. doi: 10.1016/j.celrep.2019.07.039
10. Leng T, Akther HD, Hackstein CP, Powell K, King T, Friedrich M, et al. TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions. Cell Rep (2019) 28(12):3077–91 e5. doi: 10.1016/j.celrep.2019.08.050
11. Lamichhane R, Schneider M, de la Harpe SM, Harrop TWR, Hannaway RF, Dearden PK, et al. TCR- or cytokine-activated CD8(+) mucosal-associated invariant T cells are rapid polyfunctional effectors that can coordinate immune responses. Cell Rep (2019) 28(12):3061–76 e5. doi: 10.1016/j.celrep.2019.08.054
12. Provine NM, Amini A, Garner LC, Spencer AJ, Dold C, Hutchings C, et al. MAIT cell activation augments adenovirus vector vaccine immunogenicity. Science (2021) 371(6528):521–6. doi: 10.1126/science.aax8819
13. Leeansyah E, Ganesh A, Quigley MF, Sonnerborg A, Andersson J, Hunt PW, et al. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood (2013) 121(7):1124–35. doi: 10.1182/blood-2012-07-445429
14. Cosgrove C, Ussher JE, Rauch A, Gartner K, Kurioka A, Huhn MH, et al. Early and nonreversible decrease of CD161++/MAIT cells in HIV infection. Blood (2013) 121(6):951–61. doi: 10.1182/blood-2012-06-436436
15. Fernandez CS, Amarasena T, Kelleher AD, Rossjohn J, McCluskey J, Godfrey DI, et al. MAIT cells are depleted early but retain functional cytokine expression in HIV infection. Immunol Cell Biol (2015) 93(2):177–88. doi: 10.1038/icb.2014.91
16. Greathead L, Metcalf R, Gazzard B, Gotch F, Steel A, Kelleher P. CD8+/CD161++ mucosal-associated invariant T-cell levels in the colon are restored on long-term antiretroviral therapy and correlate with CD8+ T-cell immune activation. AIDS (2014) 28(11):1690–2. doi: 10.1097/QAD.0000000000000351
17. Martin E, Treiner E, Duban L, Guerri L, Laude H, Toly C, et al. Stepwise development of MAIT cells in mouse and human. PloS Biol (2009) 7(3):e54. doi: 10.1371/journal.pbio.1000054
18. Dusseaux M, Martin E, Serriari N, Peguillet I, Premel V, Louis D, et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood (2011) 117(4):1250–9. doi: 10.1182/blood-2010-08-303339
19. Chen Z, Wang H, D’Souza C, Sun S, Kostenko L, Eckle SB, et al. Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Mucosal Immunol (2017) 10(1):58–68. doi: 10.1038/mi.2016.39
20. Wang H, Nelson AG, Wang B, Zhao Z, Lim XY, Shi M, et al. The balance of interleukin-12 and interleukin-23 determines the bias of MAIT1 versus MAIT17 responses during bacterial infection. Immunol Cell Biol (2022) 100(7):547–61. doi: 10.1111/imcb.12556
Keywords: MAIT cells, metabolite antigens, MR1, microbiome, viral infection, mouse models, immune cell interaction
Citation: Corbett AJ, Ussher JE and Hinks TSC (2023) Editorial: MAIT cells come of age. Front. Immunol. 14:1281881. doi: 10.3389/fimmu.2023.1281881
Received: 23 August 2023; Accepted: 28 August 2023;
Published: 06 September 2023.
Edited and Reviewed by:
Mariolina Salio, Immunocore, United KingdomCopyright © 2023 Corbett, Ussher and Hinks. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alexandra J. Corbett, Y29yYmV0dGFAdW5pbWVsYi5lZHUuYXU=; James E. Ussher, amFtZXMudXNzaGVyQG90YWdvLmFjLm56; Timothy S. C. Hinks, dGltb3RoeS5oaW5rc0BuZG0ub3guYWMudWs=