Thymic epithelial cells (TECs), derived from polarized two-dimensional (2D) oriented endodermal cells, are distinguished from other epithelial cells by their unique three-dimensional (3D) phenotype. ...However, some polarized epithelial cells remain present in the normal thymus, forming thymic cysts at the cortico-medullary junction. Here, we analyse the dynamics, origin and phenotype of such thymic cysts. In time-course experiments, we show a reverse correlation between thymic cyst expansion and the presence of thymocytes, suggesting a default pathway for the development of TECs in the absence of thymocytes. By transplanting isolated TEC populations into E15 fetal thymic lobes, we provide evidence that medullary thymic epithelial cells (mTECs), rather than cortical thymic epithelial cells (cTECs) contribute to the formation of thymic cysts. Finally, thymi of reporter mice reveal that the cysts originate from epithelia committed to a thymic fate, as indicated by the expression of Foxn1. The 2D-phenotype of cyst-lining TECs is not caused by a downregulation of Foxn1 expression, since a significant proportion of these cells in the embryonic and adult thymus continues to express Foxn1 at the protein level.
Signals mediated by the transforming growth factor-β superfamily of growth factors have been implicated in thymic epithelial cell (TEC) differentiation, homeostasis, and function, but a direct ...reliance on these signals has not been established. Here we demonstrate that a block in canonical transforming growth factor-β signaling by the loss of Smad4 expression in TECs leads to qualitative changes in TEC function and a progressively disorganized thymic microenvironment. Moreover, the number of thymus resident early T-lineage progenitors is severely reduced in the absence of Smad4 expression in TECs and directly correlates with extensive thymic and peripheral lymphopenia. Our observations hence place Smad4 within the signaling events in TECs that determine total thymus cellularity by controlling the number of early T-lineage progenitors.
The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly ...characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymic-fated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24⁺ progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire- and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression.
T lymphocytes of the alpha/beta T-cell receptor (TCR) lineage mature in the thymus, where they undergo a series of differentiation, expansion and selection events. For normal T-cell ontogeny to ...occur, thymocytes must interact physically with cortical and medullary thymic stroma cells. In parallel, interactions of the thymic stromal cells with TCR-positive thymocytes are necessary for the development of the thymic medulla. Comparable requirements for the differentiation of the cortex have not been defined, however. Here we analyse mutant mouse strains to assess the function of early prothymocytes in the induction of the thymic cortex. We find that animals with a developmental block at the earliest stage of T-lineage commitment lack a functional thymic cortex. This abnormality could be corrected in fetal but not adult animals by transplantation of either fetal or adult wild-type haematopoietic stem cells. Thus a developmentally restricted interaction of fetal stromal cells with early prothymocytes is required for the induction of a cortical microenvironment. In addition, a normal thymic architecture is necessary for sustained T-cell ontogeny.
Over time, the participants and organizers of the individual meetings realized that their coordination was both logical and mutually beneficial to all. ...it was agreed that from 2005, each of these ...meetings should be held every four years, and from this year, the meetings are coordinated by the unified governing board, composed of representative organizers of each of the conferences (see list of authors of this article).
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A pool of immature T cells with a seemingly unrestricted repertoire of antigen specificities is generated life‐long in the thymus. Amongst these cells are, however, thymocytes that express a ...strongly self‐reactive antigen receptor and hence hold the potential to trigger autoimmunity. To prevent such an outcome, the thymus employs several independent but functionally related strategies that act in parallel to enforce self‐tolerance. The deletion of strongly self‐reactive thymocytes and the generation of regulatory T cells constitute the two most efficient mechanisms to induce and maintain immunological tolerance. Thymic epithelial cells of the medulla express for this purpose tissue‐restricted self‐antigens. This review will focus on the cellular and molecular mechanisms operative in the thymus to shape a repertoire of mature T cells tolerant to self‐antigens.
Regulatory T (Treg) cells are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic, and homeostatic T-cell responses. Here, we report that the increase in ...Treg-cell suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103 super(pos)ICOS super(pos) Treg cells. Though present in the thymus, CD103 super(pos)ICOS super(pos) Treg cells are not generated there but recirculate from the periphery to that site. The acquisition and maintenance of this distinctive phenotype requires the LN microenvironment and the in situ availability of antigen. Contrary to conventional effector and other Treg cells, the cellularity of CD103 super(pos)ICOS super(pos) Treg cells is not affected by the absence of IL-7 and thymic stroma lymphopoetin. Given their increased frequency in lymphopenia, the absolute number of CD103 super(pos)ICOS super(pos) Treg cells remains unchanged in the periphery irrespective of a paucity of total Treg cells. We furthermore demonstrate, with cell transfers in mice, that the CD103 super(pos)ICOS super(pos) phenotype represents a LN-specific differentiation stage arrived at by several other Treg-cell subsets. Thus, tissue-specific cues determine the overall potency of the peripheral Treg-cell pool by shaping its subset composition.
T cell development and selection require the fully mature and diverse epithelial microenvironment of the thymus. Acquisition of these characteristics is dependent on expression of the forkhead (also ...known as winged-helix) transcription factor FoxN1, as a lack of functional FoxN1 results in aberrant epithelial morphogenesis and an inability to attract lymphoid precursors to the thymus primordium. However, the transcriptional control of Foxn1 expression has not been elucidated. Here we report that secreted Wnt glycoproteins, expressed by thymic epithelial cells and thymocytes, regulate epithelial Foxn1 expression in both autocrine and paracrine fashions. Wnt molecules therefore provide regulatory signals critical for thymic function.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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![TGF-[beta] type II receptor...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0953-8178/small "TGF-[beta] type II receptor expression in thymic epithelial cells inhibits the development of Hassall's corpuscles in mice")
