Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population
- Authors: Coquet, Jonathan , Chakravarti, Sumone , Kyparissoudis, Konstantinos , McNab, Finlay , Pitt, Lauren , McKenzie, Brent , Berzins, Stuart , Smyth, Mark , Godfrey, Dale
- Date: 2008
- Type: Text , Journal article
- Relation: Proceedings of the National Academy of Sciences of the United States of America Vol. 105, no. 32 (August 2008 2008), p. 11287-11292
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- Description: NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4-NK1.1 - NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4-NK1.1+ but not into CD4 +NK1.1+ NKT cells, indicating that CD4-NK1. 1- NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4+ and CD4- NKT cell sublineages.
- Description: C1
The NF-κB1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties
- Authors: Gugasyan, Raffi , Horat, Elisha , Kinkel, Sarah , Ross, Fiona , Grigoriadis, George , Gray, Daniel , O'Keeffe, Meredith , Berzins, Stuart , Belz, Gabrielle , Grumont, Raelene , Banerjee, Ashish , Strasser, Andreas , Godfrey, Dale , Tsichlis, Phillip , Gerondakis, Steve
- Date: 2012
- Type: Text , Journal article
- Relation: EMBO Journal Vol. 31, no. 3 (2012), p. 692-706
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- Description: The role of specific members of the NF-κB family of transcription factors in CD8 T-cell selection and development is largely unknown. Here, we show that mice lacking NF-κB1 develop a unique population of conventional CD8 single-positive (SP) thymocytes with memory T cell-like properties that populate peripheral immune organs. Development of this memory-like population is not due to PLZF + thymocytes and instead coincides with changes in CD8 T-cell selection. These include a reduction in the efficiency of negative selection and a dependence on MHC class Ia or Ib expressed by haematopoietic cells. These findings indicate that NF-κB1 regulates multiple events in the thymus that collectively inhibit the excess development of CD8 + thymocytes with memory cell characteristics. © 2012 European Molecular Biology Organization | All Rights Reserved.
Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients
- Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
- Date: 2010
- Type: Text , Journal article
- Relation: Leukemia Vol. 24, no. 3 (2010), p. 592-600
- Full Text: false
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- Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function. © 2010 Macmillan Publishers Limited All rights reserved.
Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients
- Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
- Date: 2010
- Type: Text , Journal article
- Relation: Leukemia Vol. 24, no. 3 (2010), p. 592
- Full Text: false
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- Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function.
Developing NKT cells need their (E) protein
- Authors: Chan, Angela , Berzins, Stuart , Godfrey, Dale
- Date: 2010
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 88, no. 5 (July 2010 2010), p. 507-509
- Full Text: false
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- Description: C1
A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage
- 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
- 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
- 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.
The glucocorticoid receptor 1A3 promoter correlates with high sensitivity to glucocorticoid-induced apoptosis in human lymphocytes
- Authors: Liddicoat, Douglas , Kyparissoudis, Konstantinos , Berzins, Stuart , Cole, Timothy , Godfrey, Dale
- Date: 2014
- Type: Text , Journal article
- Relation: Immunology and Cell Biology Vol. 92, no. 10 (2014), p. 825-836
- Full Text: false
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- Description: Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells>thymocytes/natural killer (NK) cells>peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16 + CD56 int (cytotoxic) NK cells being highly resistant to GICD, whereas CD16-CD56 hi (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and-resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD. © 2014 Australasian Society for Immunology Inc.
NKT cell development in the absence of the autoimmune regulator gene (Aire)
- Authors: Pitt, Lauren , Hubert, Francois-Xavier , Scott, Hamish , Godfrey, Dale , Berzins, Stuart
- Date: 2008
- Type: Text , Journal article
- Relation: European Journal of Immunology Vol. 38, no. 10 (2008), p. 2689-2696
- Full Text: false
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- Description: Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP31 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence self-tolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.
- Description: C1
Ex-vivo analysis of human Natural Killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4- subsets
- Authors: Chan, Angela , Leeansyah, Edwin , Cochrane, Andrew , d'Udekem, Yves , Mittag, Diana , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
- Date: 2013
- Type: Text , Journal article
- Relation: Clinical and Experimental Immunology Vol. 172, no. 1 (2013), p. 129-137
- Full Text: false
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- Description: Summary: Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4+ and CD4- human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4+ and CD4- NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4+ and CD4- subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells. © 2012 British Society for Immunology.
- Description: 2003010856
Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family
- Authors: Chan, Angela , Serwecinska, Liliana , Cochrane, Andrew , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
- Date: 2009
- Type: Text , Journal article
- Relation: Clinical and Experimental Immunology Vol. 156, no. 2 (May 2009 2009), p. 238-245
- Full Text: false
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- Description: Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.
- Description: C1
Control points in NKT-cell development
- Authors: Godfrey, Dale , Berzins, Stuart
- Date: 2007
- Type: Text , Journal article
- Relation: Nature Reviews Immunology Vol. 7, no. 7 (July 2007 2007), p. 505-518
- Full Text: false
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- Description: CD1d-dependent natural killer T (NKT) cells are a unique T-cell subset with the ability to regulate the immune system in response to a broad range of diseases. That low NKT-cell numbers are associated with many different disease states in mice and humans, combined with the fact that NKT-cell numbers vary widely between individuals, makes it crucial to understand how these cells develop and how their numbers are maintained. Here, we review the current state of knowledge of NKT-cell development and attempt to highlight the most important questions in this field.
- Description: C1
A divergent transcriptional landscape underpins the development and functional branching of MAIT cells
- 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, Chris , 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
- Reviewed:
- 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.
Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy
- Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, Kellie , Quach, Hang , Prince, Henry , Harrison, Simon , Godfrey, Dale , Ritchie, David , Berzins, Stuart
- Date: 2014
- Type: Text , Journal article
- Relation: Clinical and Experimental Immunology Vol. 175, no. 1 (2014), p. 49-58
- Full Text: false
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- Description: The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation.