Thymic Stromal Cells (thymic + stromal_cell)

Distribution by Scientific Domains


Selected Abstracts


Onset of promiscuous gene expression in murine fetal thymus organ culture

IMMUNOLOGY, Issue 3 2006
Renato Sousa Cardoso
Summary T-cell differentiation and induction of tolerance to self-antigens occurs mainly in the thymus. Thymic stromal cells, specifically medullary thymic epithelial cells, express a diverse set of genes encoding parenchymal organ-specific proteins. This phenomenon has been termed promiscuous gene expression (PGE) and has been implicated in preventing organ-specific autoimmunity by inducing T-cell tolerance to self antigens. Early thymopoiesis and the critical factors involved in T-cell differentiation can be reproduced in vitro by murine fetal thymus organ culture (FTOC), which mimics the natural thymic microenvironment. To evaluate the occurrence of PGE in FTOC, gene expression profiling during in vitro thymic development in BALB/c mice was performed using a set of nylon cDNA microarrays containing 9216 sequences. The statistical analysis of the microarray data (sam program) revealed the temporal repression and induction of 57 parenchymal and seven lymphoid organ-specific genes. Most of the genes analysed are repressed during early thymic development (15,17 days post-coitum). The expression of the autoimmune regulator (AIRE) gene at 16 days post-coitum marks the onset of PGE. This precedes the induction of parenchymal organ genes during the late developmental phase at 20 days post-coitum. The mechanism of T-cell tolerance induction begins during fetal development and continues into adulthood. Our findings are significant because they show a fine demarcation of PGE onset, which plays a central role in induction of T-cell tolerance. [source]


Thymic stromal cells and positive selection

APMIS, Issue 7-8 2001
Ann R. Chidgey
The intrathymic differentiation events leading to the development and export of mature T cells tolerant to self yet capable of responding to foreign peptide antigen in the context of self-MHC are clearly both dynamic and complex. The changing phenotype of the developing thymocyte as it migrates through and interacts with the heterogeneous thymic microenvironment and the intracellular signalling events associated with such interactions are being extensively studied, yet many aspects remain poorly defined, such as the precise relationship between stromal cells and thymic selection. Positive and negative selection are crucial events in the development of T cells, leading to a diverse yet non-autoreactive immune system. A breakdown in either of these processes could lead to either a reduced T cell repertoire or the escape into the periphery of autoreactive T cells , both clearly having deleterious consequences for the health of the individual. This review aims to summarise the current status of research in thymic positive selection with emphasis on the role of different cell types and peptides. [source]


Thymic epithelial cells provide Wnt signals to developing thymocytes

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2003
Judit Pongracz
Abstract Interactions with thymic stromal cells are known to be critical for the development of T,cells from progenitors entering the thymus, yet the molecular mechanisms of stromal cell function remain poorly understood. Accumulating evidence has highlighted the importance of ,-catenin-mediated activation of T,cell factor (TCF)/lymphoid enhancer factor (LEF) transcription during thymocyte development. As regulation of this signaling pathway is controlled by binding of soluble Wnt proteins to cell surface Frizzled (Fz) receptors, we studied components of Wnt/Fz-mediated signaling in thecontext of stromal cell regulation of thymocyte development. We show that mRNA for a variety of Wnt family members, notably Wnt-4, Wnt-7a and 7b, and Wnt-10a and 10b, are expressed by thymic epithelium rather then by thymocytes, while thymocytes demonstrate a developmentally regulated pattern of Fz receptor expression. Collectively these findings suggest (1) a functional role for Wnt-producing thymic epithelium in determining TCF/LEF-mediated transcriptional regulation in Fz-bearing thymocytes, and (2) a role for defined Wnt-Fz interactions at successive stages of thymocyte maturation. In support of this we show that separation of thymocytes from Wnt-producing epithelial cells and the thymic microenvironment, triggers ,-catenin phosphorylation and degradation in thymocytes. Thus, sustained exposure to Wnt in the context of an intact stromal microenvironment is necessary for stabilization of ,-catenin-mediated signaling in thymocytes. [source]


Establishment and functioning of intrathymic microenvironments

IMMUNOLOGICAL REVIEWS, Issue 1 2006
Graham Anderson
Summary:, The thymus supports the production of self-tolerant T cells from immature precursors. Studying the mechanisms regulating the establishment and maintenance of stromal microenvironments within the thymus therefore is essential to our understanding of T-cell production and ultimately immune system functioning. Despite our ability to phenotypically define stromal cell compartments of the thymus, the mechanisms regulating their development and the ways by which they influence T-cell precursors are still unclear. Here, we review recent findings and highlight unresolved issues relating to the development and functioning of thymic stromal cells. [source]


Thymic generation and regeneration

IMMUNOLOGICAL REVIEWS, Issue 1 2003
Jason Gill
Summary:, The thymus is a complex epithelial organ in which thymocyte development is dependent upon the sequential contribution of morphologically and phenotypically distinct stromal cell compartments. It is these microenvironments that provide the unique combination of cellular interactions, cytokines, and chemokines to induce thymocyte precursors to undergo a differentiation program that leads to the generation of functional T cells. Despite the indispensable role of thymic epithelium in the generation of T cells, the mediators of this process and the differentiation pathway undertaken by the primordial thymic epithelial cells are not well defined. There is a lack of lineage-specific cell-surface-associated markers, which are needed to characterize putative thymic epithelial stem cell populations. This review explores the role of thymic stromal cells in T-cell development and thymic organogenesis, as well as the molecular signals that contribute to the growth and expansion of primordial thymic epithelial cells. It highlights recent advances in these areas, which have allowed for a lineage relationship amongst thymic epithelial cell subsets to be proposed. While many fundamental questions remain to be addressed, collectively these works have broadened our understanding of how the thymic epithelium becomes specialized in the ability to support thymocyte differentiation. They should also facilitate the development of novel, rationally based therapeutic strategies for the regeneration and manipulation of thymic function in the treatment of many clinical conditions in which defective T cells have an important etiological role. [source]


Visualizing thymocyte motility using 2-photon microscopy

IMMUNOLOGICAL REVIEWS, Issue 1 2003
Ellen A. Robey
Summary:, Our view of a thymocyte based on its behavior in tissue culture and appearance in fixed tissue sections was of a round sessile cell. Its travel through the thymus might occur slowly, perhaps even passively, leaving it in contact with the support cells that happened to be in its immediate environment. However, when we got our first look at the behavior of thymocytes in a 3D cellular stromal cell environment, that picture changed dramatically. Instead we found that thymocytes are actively crawling, allowing them to explore their environment over relatively long distances and interact with peptide-major histocompatibility complex (pMHC)-bearing thymic stromal cells in both dynamic and stable modes. In this review, we discuss the implications of thymocyte motility for T-cell repertoire selection and for the mechanisms that determine the spatial organization of thymocyte subsets within the thymus. [source]


Thiazolidinedione treatment and constitutive-PPAR, activation induces ectopic adipogenesis and promotes age-related thymic involution

AGING CELL, Issue 4 2010
Yun-Hee Youm
Summary Age-related thymic involution is characterized by reduction in T cell production together with ectopic adipocyte development within the hematopoietic and thymic niches. Peroxisome proliferator-activated receptor gamma (PPAR,) is required for adipocyte development, glucose homeostasis and is a target for several insulin-sensitizing drugs. Our prior studies showed that age-related elevation of PPAR, expression in thymic stromal cells is associated with thymic involution. Here, using clinically relevant pharmacological and genetic manipulations in mouse models, we provide evidence that activation of PPAR, leads to reduction in thymopoiesis. Treatment of aged mice with antihyperglycemic PPAR,-ligand class of thiazolidinedione drug, rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naïve T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPAR, activation induces thymic involution, we created transgenic mice with constitutive-active PPAR, (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPAR, transgene was expressed in thymus and in fibroblast-specific protein-1/S100A4 (FSP1+) cells, a marker of secondary mesenchymal cells. The CAPPAR, fusion protein mimicked the liganded PPAR, receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPAR, mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPAR, transgenic mice had restricted T cell receptor repertoire diversity. Collectively, our data suggest that activation of PPAR, accelerates thymic aging and thymus-specific PPAR, antagonist may forestall age-related decline in T cell diversity. [source]