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
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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.
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
High CD26 and low CD94 expression identifies an IL-23 responsive Vδ2+ T Cell subset with a MAIT cell-like transcriptional profile
- Wragg, Kathleen, Tan, Hyon, Kristensen, Anne, Nguyen-Robertson, Catriona, Kelleher, Anthony, Parsons, Matthew, Wheatley, Adam, Berzins, Stuart, Pellicci, Daniel, Kent, Stephen, Juno, Jennifer
- Authors: Wragg, Kathleen , Tan, Hyon , Kristensen, Anne , Nguyen-Robertson, Catriona , Kelleher, Anthony , Parsons, Matthew , Wheatley, Adam , Berzins, Stuart , Pellicci, Daniel , Kent, Stephen , Juno, Jennifer
- Date: 2020
- Type: Text , Journal article
- Relation: Cell Reports Vol. 31, no. 11 (2020), p.
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- Description: Vδ2+ T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, phenotypically, and functionally distinct Vδ2+ T cell subsets. Despite distinct antigen specificities, CD26hiCD94lo Vδ2+ cells exhibit substantial similarities to CD26hi mucosal-associated invariant T (MAIT) cells, although CD26− Vδ2+ cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2+Vγ9+ population is dominated by CD26hiCD94lo cells; during adolescence and adulthood, Vδ2+ cells acquire CD94/NKG2A expression and the relative frequency of the CD26hiCD94lo subset declines. Critically, exposure of the CD26hiCD94lo subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26hiCD94lo Vδ2+ cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer. Wragg et al. identify a population of human gd T cells with striking similarities to MAIT cells. These cells dominate the cord blood Vd2 population and upregulate an effector-like program upon antigen and IL-23 stimulation, providing a potential mechanism by which cytotoxic Vd2 cells may accumulate during adolescence and adulthood. © 2020
- Description: National Health and Medical Research Council, NHMRC
- Authors: Wragg, Kathleen , Tan, Hyon , Kristensen, Anne , Nguyen-Robertson, Catriona , Kelleher, Anthony , Parsons, Matthew , Wheatley, Adam , Berzins, Stuart , Pellicci, Daniel , Kent, Stephen , Juno, Jennifer
- Date: 2020
- Type: Text , Journal article
- Relation: Cell Reports Vol. 31, no. 11 (2020), p.
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- Description: Vδ2+ T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, phenotypically, and functionally distinct Vδ2+ T cell subsets. Despite distinct antigen specificities, CD26hiCD94lo Vδ2+ cells exhibit substantial similarities to CD26hi mucosal-associated invariant T (MAIT) cells, although CD26− Vδ2+ cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2+Vγ9+ population is dominated by CD26hiCD94lo cells; during adolescence and adulthood, Vδ2+ cells acquire CD94/NKG2A expression and the relative frequency of the CD26hiCD94lo subset declines. Critically, exposure of the CD26hiCD94lo subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26hiCD94lo Vδ2+ cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer. Wragg et al. identify a population of human gd T cells with striking similarities to MAIT cells. These cells dominate the cord blood Vd2 population and upregulate an effector-like program upon antigen and IL-23 stimulation, providing a potential mechanism by which cytotoxic Vd2 cells may accumulate during adolescence and adulthood. © 2020
- Description: National Health and Medical Research Council, NHMRC
Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis
- Mitchell, Jenée, Kvedaraite, Egle, von Bahr Greenwood, Tatiana, Henter, Jan-Inge, Pellicci, Daniel, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2018
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 8, no. 1 (2018), p. 1-13
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- Description: Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.
Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2018
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 8, no. 1 (2018), p. 1-13
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- Description: Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.
- 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.
- Mitchell, Jenée, Kelly, Jason, Kvedaraite, E., von Bahr Greenwood, Tatiana, Henter, Jan-Inge, Pellicci, Daniel, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Kelly, Jason , Kvedaraite, E. , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2020
- Type: Text , Journal article
- Relation: Clinical Immunology Vol. 215, no. (2020), p.
- Full Text: false
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- Description: Langerhans cell histiocytosis (LCH) lesions contain myeloid lineage ‘LCH’ cells. Regulatory T cells (Tregs) are also enriched within lesions, although their role in LCH pathogenesis is unknown. LCH cells are thought to produce the transforming growth factor beta (TGF-β) within lesions, however whether Tregs contribute is unestablished. Using flow cytometry, we analyzed relative frequencies of live Tregs from LCH patients and identified CD56 expression and TGF-β production by lesion Tregs. While CD56+ Tregs were enriched in lesions, overall CD56+ T cells were reduced in the blood from active LCH patients compared to non-active disease patients, and there was a negative correlation between CD8+CD56+ T cells and Tregs. We propose that inducing a Treg phenotype in T cells such as CD56+ T cells may be a mechanism by which LCH cells divert inflammatory T cell responses. Thus, Tregs within LCH lesions are likely an important component in LCH pathogenesis. © 2020
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.
A high-dimensional cytometry atlas of peripheral blood over the human life span
- Jalali, Sedigheh, Harpur, Christopher, Piers, Adam, Auladell, Maria, Perriman, Louis, Li, Shuo, An, Kim, Anderson, Jeremy, Berzins, Stuart, Licciardi, Paul, Ashhurst, Thomas, Konstantinov, Igor, Pellicci, Daniel
- Authors: Jalali, Sedigheh , Harpur, Christopher , Piers, Adam , Auladell, Maria , Perriman, Louis , Li, Shuo , An, Kim , Anderson, Jeremy , Berzins, Stuart , Licciardi, Paul , Ashhurst, Thomas , Konstantinov, Igor , Pellicci, Daniel
- Date: 2022
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 100, no. 10 (2022), p. 805-821
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- Description: Age can profoundly affect susceptibility to a broad range of human diseases. Children are more susceptible to some infectious diseases such as diphtheria and pertussis, while in others, such as coronavirus disease 2019 and hepatitis A, they are more protected compared with adults. One explanation is that the composition of the immune system is a major contributing factor to disease susceptibility and severity. While most studies of the human immune system have focused on adults, how the immune system changes after birth remains poorly understood. Here, using high-dimensional spectral flow cytometry and computational methods for data integration, we analyzed more than 50 populations of immune cells in the peripheral blood, generating an immune cell atlas that defines the healthy human immune system from birth up to 75 years of age. We focused our efforts on children under 18 years old, revealing major changes in immune cell populations after birth and in children of schooling age. Specifically, CD4+ T effector memory cells, V
- Authors: Jalali, Sedigheh , Harpur, Christopher , Piers, Adam , Auladell, Maria , Perriman, Louis , Li, Shuo , An, Kim , Anderson, Jeremy , Berzins, Stuart , Licciardi, Paul , Ashhurst, Thomas , Konstantinov, Igor , Pellicci, Daniel
- Date: 2022
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 100, no. 10 (2022), p. 805-821
- Full Text:
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- Description: Age can profoundly affect susceptibility to a broad range of human diseases. Children are more susceptible to some infectious diseases such as diphtheria and pertussis, while in others, such as coronavirus disease 2019 and hepatitis A, they are more protected compared with adults. One explanation is that the composition of the immune system is a major contributing factor to disease susceptibility and severity. While most studies of the human immune system have focused on adults, how the immune system changes after birth remains poorly understood. Here, using high-dimensional spectral flow cytometry and computational methods for data integration, we analyzed more than 50 populations of immune cells in the peripheral blood, generating an immune cell atlas that defines the healthy human immune system from birth up to 75 years of age. We focused our efforts on children under 18 years old, revealing major changes in immune cell populations after birth and in children of schooling age. Specifically, CD4+ T effector memory cells, V
A three-stage developmental pathway for human V
- Perriman, Louis, Tavakolinia, Naeimeh, Jalali, Sedigheh, Li, Shuo, Hickey, Peter, Amann-Zalcenstein, Daniela, Ho, William, Baldwin, Tracey, Piers, Adam, Konstantinov, Igor, Anderson, Jeremy, Stanley, Edouard, Licciardi, Paul, Kannourakis, George, Naik, Shalin, Koay, Hui-Fern, Mackay, Laura, Berzins, Stuart, Pellicci, Daniel
- Authors: Perriman, Louis , Tavakolinia, Naeimeh , Jalali, Sedigheh , Li, Shuo , Hickey, Peter , Amann-Zalcenstein, Daniela , Ho, William , Baldwin, Tracey , Piers, Adam , Konstantinov, Igor , Anderson, Jeremy , Stanley, Edouard , Licciardi, Paul , Kannourakis, George , Naik, Shalin , Koay, Hui-Fern , Mackay, Laura , Berzins, Stuart , Pellicci, Daniel
- Date: 2023
- Type: Text , Journal article
- Relation: Science Immunology Vol. 8, no. 85 (2023), p.
- Full Text: false
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- Description: V
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