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| Open AccessOVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
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Article
| Open AccessThe alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration
Although thymic function declines with age, the thymus also has the ability to regenerate following injury. Here, the authors demonstrate that IL-33 and type-2 innate lymphoid cells trigger the expansion of eosinophils following radiation injury, which in turn produce IL-4 to stimulate the recovery of the thymus mesenchyme during thymus regeneration.
- Emilie J. Cosway
- , Kieran D. James
- & Graham Anderson
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| Open AccessCombined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells
T cell development requires functionally diverse thymic epithelial cell (TEC) populations performing specific functions. Here, using massively parallel flow cytometry and machine learning, the authors examine in mice the TEC compartment from the perinatal period to adulthood, identify novel phenotypic markers and characterize the function of perinatal cortical TEC.
- Fabian Klein
- , Clara Veiga-Villauriz
- & Georg A. Holländer
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| Open AccessEmbryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla
Although the importance of thymic epithelial cells (TEC) in thymus physiology is established, the development of functionally diverse TEC populations remains incompletely understood. Here, using fate-mapping experiments in the embryonic thymus, the authors identify keratin19+ multipotent progenitor cells that support medullary TEC diversity in adulthood.
- Beth Lucas
- , Andrea J. White
- & Graham Anderson
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| Open AccessIdentification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis
Knowledge about the ontogeny of T cells in the thymus relies heavily on mouse studies because of difficulty to obtain human material. Here the authors perform a single cell analysis of thymocytes from human fetal and paediatric thymic samples to characterise the development of human γδ T cells in the thymus.
- Guillem Sanchez Sanchez
- , Maria Papadopoulou
- & David Vermijlen
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Article
| Open AccessThe immune landscape of human thymic epithelial tumors
Thymic epithelial tumours represent a heterogenous group of malignancies with varied immune cell infiltration and prognosis. Here authors systematically analyze the phenotypes of both epithelial and immune cells that form these tumours, and identify three major subtypes with different T cell involvement that might affect prognosis.
- Zhongwei Xin
- , Mingjie Lin
- & Pin Wu
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Article
| Open AccessMyasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma
Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases.
- Yoshiaki Yasumizu
- , Naganari Ohkura
- & Hideki Mochizuki
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Article
| Open AccessSpecialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules
T cells are selected in the thymus, through interaction with self-antigens, to remove autoreactive cells. Here the authors show that a specialized thymic dendritic cell subset juxtaposes to microvessels, requires CX3CR1/CX3CL1 for this positioning, and has processes extruding into the blood stream to sample soluble macromolecules and assist in T cell selection.
- Elisabeth H. Vollmann
- , Kristin Rattay
- & Ulrich H. von Andrian
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Article
| Open AccessIndispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2
Development of the T cells requires functions from thymic epithelial cells, whose development and function are epigenetically regulated. Here the authors show that inactivation of the polycomb repressive complex 2 (PRC2) alters the H3K27me3 configuration, reduces TEC functions, reveals a specific TEC subset, and hampers T cell development.
- Thomas Barthlott
- , Adam E. Handel
- & Georg A. Holländer
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Article
| Open AccessClassical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells
Conventional T cell subsets are selected in the thymus by peptide bearing MHC expressed by cortical epithelial cells, in contrast cortical thymocytes express non-peptide bearing MHC molecules including CD1d and MR1 and select iNKT and MAIT cell populations respectively. Here, the authors generate a novel inducible MHC class-I trasnactivator murine system and suggest the absence of peptide-MHC on thymocytes is involved in the selection of non-peptide specific lymphocytes.
- Hristo Georgiev
- , Changwei Peng
- & Kristin A. Hogquist
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Article
| Open AccessSingle-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla
The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.
- Jhoanne L. Bautista
- , Nathan T. Cramer
- & Audrey V. Parent
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Article
| Open AccessReconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds
The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.
- Sara Campinoti
- , Asllan Gjinovci
- & Paola Bonfanti
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| Open AccessSingle-cell RNA sequencing identifies shared differentiation paths of mouse thymic innate T cells
Innate T cells such as iNKT, MAIT and γδ T cells all develop in the thymus, but their differentiation paths are still unclear. Here, the authors show, using single-cell RNA sequencing, that all three cell types develop via shared and branched differentiation paths that are corroborated by additional results from gene-deficient mice and human liver T cells.
- Minji Lee
- , Eunmin Lee
- & You Jeong Lee
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Article
| Open AccessDifferential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates
T cell tolerance is established in the thymus via interactions with medullary thymic epithelial cells (mTEC) expressing tissue-restricted self antigens. Here, the authors suggest, using new transgenic mouse lines and single cell transcriptome analyses, that specific mTEC subsets are associated with distinct T cell fates.
- Marie-Ève Lebel
- , Marie Coutelier
- & Heather J. Melichar
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Article
| Open AccessDiversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells
Thymus is a unique environment hosting the development of many T cell subsets with distinct functions. Here the authors show that medullary thymic epithelial cells (mTEC) are functionally diverse, with LTβR signaling serving differential regulation of mTEC for specific control of multiple lineages of invariant natural killer T cells.
- Beth Lucas
- , Andrea J. White
- & Graham Anderson
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Article
| Open AccessMyc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth
Thymic epithelial cells (TEC) are essential for the maturation of functional T cells, while thymus size is proportional to the overall output efficiency. Here the authors show, using transcriptome analyses, that mouse fetal TEC maintain a Myc-dependent genetic program to ensure a rapid increase in thymus size, and thereby expedited T cell generation.
- Jennifer E. Cowan
- , Justin Malin
- & Avinash Bhandoola
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Article
| Open AccessDynamic changes in epithelial cell morphology control thymic organ size during atrophy and regeneration
One aspect of ageing on immunity is attributed to accelerated thymic atrophy, but the underlying mechanism is still lacking. Here the authors show, using conditional reporter mouse models, that both atrophy and regeneration of the thymus are regulated by rate-limiting morphological changes in epithelial stroma, independent of cell death or proliferation.
- Thomas Venables
- , Ann V. Griffith
- & Howard T. Petrie
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Article
| Open AccessCD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation
CD69 competes with S1P1, a chemokine receptor mediating thymocyte egress, for surface expression on thymocytes, but whether CD69 is required for normal thymic development is unclear. Here the authors show that CD69 and S1P1 synergize to control type 2 natural killer (NKT2) cells differentiation by modulating the thymic egress of NKT2 precursor.
- Motoko Y. Kimura
- , Akemi Igi
- & Toshinori Nakayama
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Article
| Open AccessRunx-dependent and silencer-independent repression of a maturation enhancer in the Cd4 gene
The commitment of helper and cytotoxic lineages for CD4 and CD8 T cells, respectively, is associated with the regulation of Cd4 gene expression. Here the authors show that an intronic silencer, S4, has differential effects and synergy with the RUNX complex to act on two enhancer elements of the CD4 gene to control T cell lineage commitment in the thymus.
- Satoshi Kojo
- , Nighat Yasmin
- & Ichiro Taniuchi
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Article
| Open AccessStage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development
The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of Cd4 in thymocytes but are dispensable for its sustained expression in peripheral T cells.
- Priya D. Issuree
- , Kenneth Day
- & Dan R. Littman
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Article
| Open AccessThree distinct developmental pathways for adaptive and two IFN-γ-producing γδ T subsets in adult thymus
Mouse γδ T cells have diverse functional subsets, but how these subsets are programmed during their development is still unclear. Here the authors show that three surface markers, CD117, CD200 and CD371, refine the development of γδ T cells in the thymus into three pathways programming distinct γδ T cell subsets.
- Terkild Brink Buus
- , Niels Ødum
- & Jens Peter Holst Lauritsen
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| Open AccessPriming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes
CD4 and CD8 T cells develop in the thymus with their transcription programs controlled by ThPOK and Runx3, respectively. Here the authors show that a pre-commitment event modulated by the transcription factor, Bcl11b, is required for the proper expression of ThPOK and Runx3 and correct CD4/CD8 lineage commitment.
- Satoshi Kojo
- , Hirokazu Tanaka
- & Ichiro Taniuchi
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Article
| Open AccessFoxn1-β5t transcriptional axis controls CD8+ T-cell production in the thymus
Foxn1 is involved in thymic epithelial cell (TEC) and CD8+T cell development. Here the authors show this development requires Foxn1 binding proximal to, and inducing transcription of, the gene encoding β5t in cortical TECs.
- Muhammad Myn Uddin
- , Izumi Ohigashi
- & Yousuke Takahama
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Article
| Open AccessDistinct gene expression patterns correlate with developmental and functional traits of iNKT subsets
A recent advance in invariant natural killer T cell (iNKT) cell biology is their classification into iNKT1, iNKT2 and iNKT17 subsets. Here the authors provide a transcriptomic analysis of these thymic subsets from Balb/c and C57Bl/6 mice that supports and extends the categorization.
- Hristo Georgiev
- , Inga Ravens
- & Günter Bernhardt
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Article
| Open AccessCXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation
T cell development has been a classical model for understanding cell fate regulation by epigenetics. Here the authors show that Cxxc1 controls thymocyte development mainly through regulating several key genes, such as Rorc, Zap70 and Cd8, which requires its H3K4me3 but not DNA methylation function.
- Wenqiang Cao
- , Jing Guo
- & Lie Wang
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Article
| Open AccessIncreased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus
The degree of Treg self-antigen reactivity varies across experimental systems. Here the authors develop a new model of skin autoimmunity and show that the size of tissue-specific Treg pool in the thymus depends on AIRE, the availability of the tissue antigen, and its presentation by dendritic cells.
- Jiqiang Lin
- , Lu Yang
- & Juan J. Lafaille
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Article
| Open AccessIntronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus
Jmjd6 is a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins. Here the authors show that Jmjd6 directs splicing of a central tolerance regulator Aire in medullary thymic epithelial cells, and that Jmjd6 deficiency leads to loss of Aire and multi-organ autoimmunity in mice.
- Toyoshi Yanagihara
- , Fumiyuki Sanematsu
- & Fukui Yoshinori
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Article
| Open AccessThymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells
Proteasomes digest intracellular proteins into peptides that are then presented to lymphocytes as antigens. Here the authors show that a thymic epithelium-specific proteasome subunit cuts model proteins in a pattern favouring their weak binding to T cell receptor, and thus T cell positive selection.
- Katsuhiro Sasaki
- , Kensuke Takada
- & Shigeo Murata
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Transdifferentiation of parathyroid cells into cervical thymi promotes atypical T-cell development
Cervical thymi are secondary sites of T-cell development in mice. Here, the authors investigate previously unknown origin of cervical thymi and show that they develop as a by-product of the normal separation of thymic and parathyroid tissue.
- Jie Li
- , Zhijie Liu
- & Nancy R. Manley
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Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output
Thymic epithelial cells provide the microenvironment required for the expansion of T cells in the thymus, but their exact function is not well understood. Here, the authors report that thymic epithelial cells are the source of matricellular protein CYR61, which is involved in thymic function and T cell development.
- Yalin Emre
- , Magali Irla
- & Beat A. Imhof
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| Open AccessExploring the MHC-peptide matrix of central tolerance in the human thymus
T cells learn to tolerate self-antigens in the thymus, where self-peptides are presented by thymic antigen-presenting cells. Here, the authors present an ex vivomass spectrometric analysis of the self-peptide repertoire associated with MHC I and II in human thymic tissue.
- Eleni Adamopoulou
- , Stefan Tenzer
- & Christina Stoeckle
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Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus
Autoreactive T cells are eliminated as they encounter self-antigens during transit through the thymus. Uedaet al. reveal that mice lacking the Hippo homologue Mst1 develop autoimmunity as a result of impaired integrin-dependent T cell migration through this negatively selective niche.
- Yoshihiro Ueda
- , Koko Katagiri
- & Tatsuo Kinashi