High CD26 and low CD94 expression identifies an IL-23 responsive Vδ2+ T Cell subset with a MAIT cell-like transcriptional profile
- 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.
- Full Text:
- Reviewed:
- 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
Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells
- Authors: Dinh, Xuyen , Stanley, Dragana , Smith, Letitia , Moreau, Morgane , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment. © 2021, The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Stuart Berzins” is provided in this record**
Presumed guilty: Natural killer T cell defects and human disease
- Authors: Berzins, Stuart , Smyth, Mark , Baxter, Alan
- Date: 2011
- Type: Text , Journal article
- Relation: Nature Reviews Immunology Vol. 11, no. 2 (February 2011 2011), p. 131-142
- Full Text: false
- Reviewed:
- Description: Abstract | Natural killer T (NKT) cells are important regulatory lymphocytes that have been shown in mouse studies, to have a crucial role in promoting immunity to tumours, bacteria and viruses, and in suppressing cell-mediated autoimmunity. Many clinical studies have indicated that NKT cell deficiencies and functional defects might also contribute to similar human diseases, although there is no real consensus about the nature of the NKT cell defects or whether NKT cells could be important for the diagnosis and/or treatment of these conditions. In this Review, we describe the approaches that have been used to analyse the NKT cell populations of various patient groups, suggest new strategies to determine how (or indeed, if) NKT cell defects contribute to human disease, and discuss the prospects for using NKT cells for therapeutic benefit.
- Description: C1
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
- Full Text:
- Reviewed:
- 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
Distinct subpopulations of DN1 thymocytes exhibit preferential gamma delta T lineage potential
- Authors: Oh, Seungyoul , Liu, Xin , Tomei, Sara , Luo, Mengxiao , Skinner, Jarrod , Berzins, Stuart , Naik, Shalin , Gray, Daniel , Chong, Mark
- Date: 2023
- Type: Text , Journal article
- Relation: Frontiers in Immunology Vol. 14, no. (2023), p.
- Full Text:
- Reviewed:
- Description: The
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
- Full Text: false
- Reviewed:
- 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.
Effect of hydralazine on angiotensin II-induced abdominal aortic aneurysm in apolipoprotein e-deficient mice
- Authors: Wang, Yutang , Sargisson, Owen , Nguyen, Dinh , Parker, Ketura , Pyke, Stephan , Alramahi, Ahmed , Thihlum, Liam , Fang, Yan , Wallace, Morgan , Berzins, Stuart , Oqueli, Ernesto , Magliano, Dianna , Golledge, Jonathan
- Date: 2023
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 24, no. 21 (2023), p.
- Relation: https://purl.org/au-research/grants/nhmrc/1062671
- Full Text:
- Reviewed:
- Description: The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100
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
- Reviewed:
- 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.
Thymic development of unconventional T cells: how NKT cells, MAIT cells and γδ T cells emerge
- 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
- Reviewed:
- 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.
Foxp3+ tregs from langerhans cell histiocytosis lesions co-express CD56 and have a definitively regulatory capacity
- 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
- Reviewed:
- 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
Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes
- Authors: Evrard, Maximilien , Wynne-Jones, Erica , Peng, Changwei , Kannourakis, George , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Journal of Experimental Medicine Vol. 219, no. 1 (2021), p.
- Full Text:
- Reviewed:
- Description: Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-β signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes. © 2021 Evrard et al.
Natural killer T cells: Drivers or passengers in preventing human disease?
- Authors: Berzins, Stuart , Richie, David
- Date: 2014
- Type: Text , Journal article
- Relation: Nature Reviews Immunology Vol. 14, no. 9 (2014), p. 640-646
- Full Text: false
- Reviewed:
- Description: Natural killer T (NKT) cells are credited with regulatory roles in immunity against cancers, autoimmune diseases, allergies, and bacterial and viral infections. Studies in mice and observational research in patient groups have suggested that NKT cell-based therapies could be used to prevent or treat these diseases, yet the translation into clinical settings has been disappointing. We support the view that NKT cells have regulatory characteristics that could be exploited in clinical settings, but there are doubts about the natural roles of NKT cells in vivo and whether NKT cell defects are fundamental drivers of disease in humans. In this Opinion article, we discuss the uncertainties and opportunities regarding NKT cells in humans, and the potential for NKT cells to be manipulated to prevent or treat disease. © 2014 Macmillan Publishers Limited.
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
- Reviewed:
- 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
- Reviewed:
- Description: C1
An NZW-derived interval on chromosome 7 moderates sialadenitis, but not insulitis in congenic nonobese diabetic mice
- Authors: Burt, Rachel , Watkins, Laura , Tan, Iris , Wang, Nancy , Quirk, Fiona , Mackin, Leanne , Morgan, Phillip , Zhang, Jian-Guo , Berzins, Stuart , Morahan, Grant , Brodnicki, Thomas
- Date: 2010
- Type: Text , Journal article
- Relation: Journal of Immunology Vol. 184, no. 2 (2010), p. 859-868
- Full Text: false
- Reviewed:
- Description: Autoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren's syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD x NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice. To examine whether Ssial3 could contribute to both diseases, or was specific for SjS, we generated a congenic mouse strain that harbored an NZW-derived Chr7 interval on the NOD genetic background. This congenic strain exhibited reduced sialadenitis compared with NOD mice and confirmed Ssial3. This reduction, however, did not ameliorate saliva abnormalities associated with SjS-like disease in NOD mice, nor were congenic mice protected against insulitis (lymphocytic infiltration of the pancreatic islets) or diabetes onset. Thus, the Ssial3 locus appears to have a tissue-specific effect for which the NZW allele is unable to prevent other autoimmune traits in the NOD mouse. Anomalous increases for antinuclear Ab production and frequency of marginal-zone B cells were also identified in congenic mice, indicating that theNZW-derived Chr7 interval has a complex effect on the NOD immune system. Copyright © 2010 by The American Association of Immunologists, Inc.
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
- 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.
Plasma signaling factors in patients with langerhans cell histiocytosis (LCH) correlate with relative frequencies of LCH cells and t cells within lesions
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Lourda, Magda , Henter, Jan-Inge , Berzins, Stuart , Kannourakis, George
- Date: 2022
- Type: Text , Journal article
- Relation: Frontiers in Pediatrics Vol. 10, no. (2022), p.
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients. Copyright © 2022 Mitchell, Kvedaraite, von Bahr Greenwood, Lourda, Henter, Berzins and Kannourakis.
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
- Full Text:
- Reviewed:
- 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
- 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.
An emerging role for immune regulatory subsets in chronic lymphocytic leukaemia
- Authors: Wallace, Morgan , Alcantara, Marice , Minoda, Yosuke , Kannourakis, George , Berzins, Stuart
- Date: 2015
- Type: Text , Journal article
- Relation: International Immunopharmacology Vol. 28, no. 2 (2015), p. 897-900
- Full Text: false
- Reviewed:
- Description: The last few years has seen the burgeoning of a new category of therapeutics for cancer targeting immune regulatory pathways. Antibodies that block the PD-1/PD-L1 interaction are perhaps the most prominent of these new anti-cancer therapies, but several other inhibitory receptor ligand interactions have also shown promise as targets in clinical trials, including CTLA-4/CD80 and Lag-3/MHC class II. Related to this is a rapidly improving knowledge of 'regulatory' lymphocyte lineages, including NKT cells, MATT cells, B regulatory cells and others. These cells have potent cytokine responses that can influence the functioning of other immune cells and many researchers believe that they could be effective targets for therapies designed to enhance immune responses to cancer. This review will outline our current understanding of FOXP3 + 'Tregs', NKT cells, MAIT cells and B regulatory cells immune regulatory cell populations in cancer, with a particular focus on chronic lymphocytic leukaemia (CLL). We will discuss evidence linking CLL with immune regulatory dysfunction and the potential for new therapies targeting regulatory cells. (C) 2015 Elsevier B.V. All rights reserved.