A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
- Koay, Hui-Fern, Gherardin, Nicholas, Enders, Anselm, Loh, Liyen, Mackay, Laura, Almeida, Catarina, Russ, Brendan, Nold-Petry, Claudia, Nold, Marcel, Bedoui, Sammy, Chen, Zhenjun, Corbett, Alexandra, Eckle, Sidonia, Meehan, Bronwyn, d'Udekem, Yves, Konstantinov, Igor, Lappas, Martha, Liu, Ligong, Goodnow, Chris, Fairlie, David, Rossjohn, Jamie, Chong, Mark, Kedzierska, Katherine, Berzins, Stuart, Belz, Gabrielle, McCluskey, James, Uldrich, Adam, Godfrey, Dale, Pellicci, Daniel
- Authors: Koay, Hui-Fern , Gherardin, Nicholas , Enders, Anselm , Loh, Liyen , Mackay, Laura , Almeida, Catarina , Russ, Brendan , Nold-Petry, Claudia , Nold, Marcel , Bedoui, Sammy , Chen, Zhenjun , Corbett, Alexandra , Eckle, Sidonia , Meehan, Bronwyn , d'Udekem, Yves , Konstantinov, Igor , Lappas, Martha , Liu, Ligong , Goodnow, Chris , Fairlie, David , Rossjohn, Jamie , Chong, Mark , Kedzierska, Katherine , Berzins, Stuart , Belz, Gabrielle , McCluskey, James , Uldrich, Adam , Godfrey, Dale , Pellicci, Daniel
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Immunology Vol. 17, no. 11 (2016), p. 1300-1311
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- Description: 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.
- Authors: Koay, Hui-Fern , Gherardin, Nicholas , Enders, Anselm , Loh, Liyen , Mackay, Laura , Almeida, Catarina , Russ, Brendan , Nold-Petry, Claudia , Nold, Marcel , Bedoui, Sammy , Chen, Zhenjun , Corbett, Alexandra , Eckle, Sidonia , Meehan, Bronwyn , d'Udekem, Yves , Konstantinov, Igor , Lappas, Martha , Liu, Ligong , Goodnow, Chris , Fairlie, David , Rossjohn, Jamie , Chong, Mark , Kedzierska, Katherine , Berzins, Stuart , Belz, Gabrielle , McCluskey, James , Uldrich, Adam , Godfrey, Dale , Pellicci, Daniel
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Immunology Vol. 17, no. 11 (2016), p. 1300-1311
- Full Text:
- Reviewed:
- Description: 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.
Human blood MAIT cell subsets defined using MR1 tetramers
- Gherardin, Nicholas, Souter, Michael, Koay, Hui-Fern, Mangas, Kirstie, Seemann, Torsten, Stinear, Timothy, Eckle, Sidonia, Berzins, Stuart, d'Udekem, Yves, Konstantinov, Igor, Fairlie, David, Ritchie, David, Neeson, Paul, Pellicci, Daniel, Uldrich, Adam, McCluskey, James, Godfrey, Dale
- Authors: Gherardin, Nicholas , Souter, Michael , Koay, Hui-Fern , Mangas, Kirstie , Seemann, Torsten , Stinear, Timothy , Eckle, Sidonia , Berzins, Stuart , d'Udekem, Yves , Konstantinov, Igor , Fairlie, David , Ritchie, David , Neeson, Paul , Pellicci, Daniel , Uldrich, Adam , McCluskey, James , Godfrey, Dale
- Date: 2018
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 96, no. 5 (2018), p. 507-525
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- Description: Mucosal-associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non-lineage-specific (surrogate) markers such as anti-TRAV1-2, CD161, IL-18R
- Authors: Gherardin, Nicholas , Souter, Michael , Koay, Hui-Fern , Mangas, Kirstie , Seemann, Torsten , Stinear, Timothy , Eckle, Sidonia , Berzins, Stuart , d'Udekem, Yves , Konstantinov, Igor , Fairlie, David , Ritchie, David , Neeson, Paul , Pellicci, Daniel , Uldrich, Adam , McCluskey, James , Godfrey, Dale
- Date: 2018
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 96, no. 5 (2018), p. 507-525
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- Description: Mucosal-associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non-lineage-specific (surrogate) markers such as anti-TRAV1-2, CD161, IL-18R
Divergent SATB1 expression across human life span and tissue compartments
- Nüssing, Simone, Koay, Hui-Fern, Sant, Sneha, Loudovaris, Thomas, Mannering, Stuart, Lappas, Martha, d′Udekem, Yves, Konstantinov, Igor, Berzins, Stuart, Rimmelzwaan, Guus, Turner, Stephen, Clemens, Bridie, Godfrey, Dale, Nguyen, Thi, Kedzierska, Katherine
- Authors: Nüssing, Simone , Koay, Hui-Fern , Sant, Sneha , Loudovaris, Thomas , Mannering, Stuart , Lappas, Martha , d′Udekem, Yves , Konstantinov, Igor , Berzins, Stuart , Rimmelzwaan, Guus , Turner, Stephen , Clemens, Bridie , Godfrey, Dale , Nguyen, Thi , Kedzierska, Katherine
- Date: 2019
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 97, no. (2019), p. 498-511
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- Description: Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8 + T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.
- Authors: Nüssing, Simone , Koay, Hui-Fern , Sant, Sneha , Loudovaris, Thomas , Mannering, Stuart , Lappas, Martha , d′Udekem, Yves , Konstantinov, Igor , Berzins, Stuart , Rimmelzwaan, Guus , Turner, Stephen , Clemens, Bridie , Godfrey, Dale , Nguyen, Thi , Kedzierska, Katherine
- Date: 2019
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 97, no. (2019), p. 498-511
- Full Text:
- Reviewed:
- Description: Special AT-rich binding protein-1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T-cell development, with SATB1-knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T-cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD-1). Thus, SATB1 expression in T-cell subsets across different tissue compartments in humans is of potential importance for targeting PD-1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD-1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen-specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T-cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine-tuned expression dynamics, which appear to be tissue- and antigen-dependent. Furthermore, SATB1 expression negatively correlates with PD-1 expression in virus-specific CD8 + T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD-1 in T cells, highly relevant to human malignancies or chronic viral infections.
- Koay, Hui-Fern, Su, Shian, Amann-Zalcenstein, Daniela, Daley, Stephen, Comerford, Iain, Miosge, Lisa, Whyte, C. E., Konstantinov, Igor, D'Udekem, Yves, Baldwin, Tracey, Hickey, P. F., Berzins, Stuart, Mak, Jeffrey, Sontani, Yovina, Roots, Carla, Sidwell, Tom, Kallies, Axel, Chen, Zhenjun, Nüssing, S., Kedzierska, Katherine, Mackay, Laura, McColl, Simone, Deenick, Elissa, Fairlie, David, McCluskey, James, Goodnow, Christopher, Ritchie, Matthew, Belz, Gabrielle, Naik, Shalin, Pellicci, Daniel, Godfrey, Dale
- Authors: Koay, Hui-Fern , Su, Shian , Amann-Zalcenstein, Daniela , Daley, Stephen , Comerford, Iain , Miosge, Lisa , Whyte, C. E. , Konstantinov, Igor , D'Udekem, Yves , Baldwin, Tracey , Hickey, P. F. , Berzins, Stuart , Mak, Jeffrey , Sontani, Yovina , Roots, Carla , Sidwell, Tom , Kallies, Axel , Chen, Zhenjun , Nüssing, S. , Kedzierska, Katherine , Mackay, Laura , McColl, Simone , Deenick, Elissa , Fairlie, David , McCluskey, James , Goodnow, Christopher , Ritchie, Matthew , Belz, Gabrielle , Naik, Shalin , Pellicci, Daniel , Godfrey, Dale
- Date: 2019
- Type: Text , Journal article
- Relation: Science Immunology Vol. 4, no. 41 (2019), p.
- Full Text: false
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- Description: MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans. Copyright © 2019 The Authors.
Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge
- Pellicci, Daniel, Koay, Hui-Fern, Berzins, Stuart
- Authors: Pellicci, Daniel , Koay, Hui-Fern , Berzins, Stuart
- Date: 2020
- Type: Text , Journal article , Review
- Relation: Nature Reviews Immunology Vol. 20, no. 12 (2020), p. 756-770
- Full Text: false
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- Description: T cell lineages are defined by specialized functions and differential expression of surface antigens, cytokines and transcription factors. Conventional CD4+ and CD8+ T cells are the best studied of the T cell subsets, but ‘unconventional’ T cells have emerged as being more abundant and influential than has previously been appreciated. Key subsets of unconventional T cells include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells; collectively, these make up ~10% of circulating T cells, and often they are the majority of T cells in tissues such as the liver and gut mucosa. Defects and deficiencies in unconventional T cells are associated with autoimmunity, chronic inflammation and cancer, so it is important to understand how their development is regulated. In this Review, we describe the thymic development of NKT cells, MAIT cells and γδ T cells and highlight some of the key differences between conventional and unconventional T cell development. © 2020, Springer Nature Limited.
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