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A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage

Nature Immunology volume 17, pages 1300–1311 (2016)Cite this article

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Abstract

Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.

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Figure 1: Identification of distinct MAIT-cell subsets in mouse thymus.
Figure 2: Ontogeny, transcriptional and functional potential of mouse MAIT cells.
Figure 3: Precursor-product relationship of mouse MAIT cells.
Figure 4: PLZF controls development of MAIT cells.
Figure 5: MAIT cell development is impaired in Drosha-deficient mice and germ-free mice.
Figure 6: CD1d-deficient mice have a greater number of MAIT cells.
Figure 7: Identification of distinct MAIT-cell subsets in humans.
Figure 8: Comparison of human MAIT cells from thymus and blood.

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Acknowledgements

We thank the staff of the University of Melbourne DMI and MBC flow cytometry facilities and M. Camilleri, D. Taylor and animal house staff for animal husbandry and assistance with genotyping; J.C. Zúñiga-Pflücker (University of Toronto) for OP9 and OP9-DL1 cells; T. Hansen (Washington University School of Medicine) for the MR1-blocking antibody 8F2.F9; and the clinical research midwives G. Christophers, G. Pell and R. Murdoch and the Obstetrics and Midwifery staffs of the Mercy Hospital for Women for assistance with collection of the cord blood samples. Supported by the National Health and Medical Research Council of Australia (1083942, 1013667 and 1016629; CDF 1035858 to A.E.; ECF 1054431 to D.G.P.; Senior Principal Research Fellowships 1020770 and 1027369 to D.I.G. and D.P.F.; Australia Fellowship AF50 to J.R.; CDF2 Fellowship 1047025 to M.C.; CDF2 Fellowship 1023294 to K.K.; and CDF1 Fellowship 1106004 to L.K.M.), the Australian Research Council (CE140100011 and LE110100106; Future Fellowship FT140100278 to A.P.U.), the Leukaemia Foundation of Australia (Postgraduate Scholarship for N.A.G.), the National Heart Foundation of Australia (Future Leader Fellowship for C.A.N.-P.), the Hudson Institute (Star Recruitment Fellowship for M.F.N.) and the Ritchie Centre (Victor Yu Fellowship for M.F.N.).

Author information

Author notes

  1. Dale I Godfrey and Daniel G Pellicci: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia

    Hui-Fern Koay, Nicholas A Gherardin, Liyen Loh, Laura K Mackay, Catarina F Almeida, Brendan E Russ, Sammy Bedoui, Zhenjun Chen, Alexandra J Corbett, Sidonia B G Eckle, Bronwyn Meehan, Katherine Kedzierska, Stuart P Berzins, James McCluskey, Adam P Uldrich, Dale I Godfrey & Daniel G Pellicci

  2. Cancer Immunology Research Program, Peter MacCallum Cancer Centre, East Melbourne, Australia

    Nicholas A Gherardin

  3. Department of Immunology, John Curtin School of Medical Research, Canberra, Australia

    Anselm Enders & Chris C Goodnow

  4. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia

    Laura K Mackay, Adam P Uldrich, Dale I Godfrey & Daniel G Pellicci

  5. Department of Paediatrics, Monash University, Clayton, Australia

    Claudia A Nold-Petry & Marcel F Nold

  6. The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia

    Claudia A Nold-Petry & Marcel F Nold

  7. Royal Children's Hospital, Flemington Road, Parkville, Australia

    Yves d'Udekem & Igor E Konstantinov

  8. Department of Obstetrics and Gynaecology, Obstetrics, Nutrition and Endocrinology Group, University of Melbourne, Heidelberg, Australia

    Martha Lappas

  9. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Australia

    Martha Lappas

  10. Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia

    Ligong Liu & David P Fairlie

  11. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Queensland, Brisbane, Australia

    Ligong Liu & David P Fairlie

  12. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

    Jamie Rossjohn

  13. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK

    Jamie Rossjohn

  14. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Australia

    Jamie Rossjohn

  15. St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia,

    Mark M Chong

  16. Department of Medicine (St Vincent's), University of Melbourne, Fitzroy, Australia.,

    Mark M Chong

  17. Collaborative Research Network, Federation University, Ballarat, Australia

    Stuart P Berzins

  18. Fiona Elsey Cancer Research Institute, Ballarat, Australia

    Stuart P Berzins

  19. The Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

    Gabrielle T Belz

  20. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Gabrielle T Belz

Authors
  1. Hui-Fern Koay
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  2. Nicholas A Gherardin
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Contributions

H.-F.K., N.A.G., C.F.A. and D.G.P. performed experiments; H.-F.K. prepared figures; A.E., L.Lo., L.K.M., B.E.R., C.A.N.-P., M.F.N., S.B., Z.C., A.J.C., S.B.G.E., B.M., Y.d.U., I.E.K., M.L., L.Li., C.C.G., D.P.F., J.R., M.M.C., K.K., S.P.B., G.T.B. and J.M. facilitated experiments and/or provided reagents and tissue samples; H.-F.K., A.P.U., D.I.G. and D.G.P. planned experiments, interpreted data and prepared the manuscript; and D.I.G. and D.G.P. led the investigation.

Corresponding authors

Correspondence to Dale I Godfrey or Daniel G Pellicci.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 RORγt expression on MAIT cells in RORγt-GFP reporter mice.

Flow cytometric analysis of MAIT cells from MR1-5-OP-RU tetramer enriched RORγt-GFP reporter mouse thymi for CD24, CD44, and GFP expression. Data are representative of a total of 9 mice with 3-pooled mouse thymi from 2 independent experiments.

Supplementary Figure 2 Thymic MAIT cell subsets in mice with transgenic expression of the TRAV1-TRAJ33 TCR.

Flow cytometric analysis of MR1-5-OP-RU tetramer reactive MAIT cells in TRAV1-TRAJ33 Cα-/- TCR transgenic mouse thymus for expression of CD4, CD8, CD24 and CD44. Data are representative of 3 independent experiments.

Supplementary Figure 3 NKT cells in Drosha-deficient mice and germ-free mice.

(a) Flow cytometric analysis of CD1d-PBS44 tetramer+ TCRβ+ NKT cells from thymus, spleen, lymph nodes from Droshafl/+ CD4-Cre heterozygous control mice and Droshafl/fl CD4-Cre mice. Absolute numbers and percentage NKT cells of TCRβ+ cells in thymus, spleen and lymph nodes of Droshafl/+ CD4-Cre heterozygous control mice and Droshafl/fl CD4-Cre mice. (b) Flow cytometric analysis of NKT cells from thymus, spleen, lymph nodes from control (SPF) mice and germ-free (GF) mice. Absolute numbers and percentage NKT cells of TCRβ+ cells in thymus and spleen of SPF mice and GF mice. *P<0.1 **P<0.01 ***P<0.001 NS = not significant (Mann-Whitney rank sum U test (a, b)). Data are representative of 3 independent experiments with a total of 8 mice per group (a; mean ± SEM) or of 2 independent experiments with a combined total of 11-15 mice per group (b; mean ± SEM).

Supplementary Figure 4 MAIT cells in IL-18-deficient mice and IL-18Rα-deficient mice.

(a) Flow cytometric analysis of MAIT cells from MR1-5-OP-RU tetramer enriched thymus, spleen and lymph nodes from WT and IL-18-deficient mice for CD24 and CD44 expression. (b) Absolute numbers and percentage MAIT cells of TCRβ+ cells in individual thymus, spleen and lymph nodes of WT and IL-18-deficient mice. (c) Flow cytometric analysis of MAIT cells from MR1-5-OP-RU tetramer enriched thymus, spleen and lymph nodes from WT and IL-18Rα-deficient mice for CD24 and CD44 expression. (d) Absolute numbers and percentage MAIT cells of TCRβ+ cells in individual thymus, spleen and lymph nodes of WT and IL-18Rα-deficient mice. *P<0.1 **P<0.01 ***P<0.001 NS = not significant (Mann-Whitney rank sum U test (b, d)). Data are representative of 3 independent experiments with a total of 12 mice per group (a, b; mean ± SEM) or 2 independent experiments with a total of 10 mice per group (c, d; mean ± SEM).

Supplementary Figure 5 MAIT cells in C57BL/6 CD1d-deficient mice.

Flow cytometric analysis of MAIT cells from thymus, MR1-5-OP-RU enriched thymus and spleen from C57BL/6 WT and C57BL/6 CD1d-deficient mice for CD24, CD44 and CD4/CD8 co-receptor expression. Data are representative of 3 independent experiments with a total of 6 mice per group.

Supplementary Figure 6 Schematic of the three development stages of MAIT cells.

Mouse and human MAIT cell development in the thymus can be defined by three separate stages. Mouse thymic MAIT cells can be defined by a three-stage sequential pathway from CD24+CD44− (stage 1), via CD24−CD44− (stage 2), to CD24−CD44+ (stage 3), while in humans thymic MAIT cells can be defined by three distinct stages from CD161−CD27− (stage 1), via CD161−CD27+ (stage 2), to CD161+CD27+/lo (stage 3). These stages are regulated by several factors including MR1, PLZF, Drosha and commensal bacteria.

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Koay, HF., Gherardin, N., Enders, A. et al. A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage. Nat Immunol 17, 1300–1311 (2016). https://doi.org/10.1038/ni.3565

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