Thymic Microenvironment (thymic + microenvironment)

Distribution by Scientific Domains


Selected Abstracts


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]


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]


Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution

AGING CELL, Issue 3 2010
Liguang Sun
Summary Age-related thymic involution may be triggered by gene expression changes in lymphohematopoietic and/or nonhematopoietic thymic epithelial cells (TECs). The role of epithelial cell-autonomous gene FoxN1 may be involved in the process, but it is still a puzzle because of the shortage of evidence from gradual loss-of-function and exogenous gain-of-function studies. Using our recently generated loxP -floxed- FoxN1(fx) mouse carrying the ubiquitous CreERT (uCreERT) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreERT -fx/fx mice showed an accelerated age-related thymic involution owing to progressive loss of FoxN1+ TECs. The thymic aging phenotypes were clearly observable as early as at 3,6 months of age, resembling the naturally aged (18,22-month-old) murine thymus. By intrathymically supplying aged wild-type mice with exogenous FoxN1-cDNA, thymic involution and defective peripheral CD4+ T-cell function could be partially rescued. The results support the notion that decline of a single epithelial cell-autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers age-related thymic involution in mice. [source]


Age-dependent changes in the nervous and endocrine control of the thymus

MICROSCOPY RESEARCH AND TECHNIQUE, Issue 2 2004
Jonas Hannestad
Abstract The immune system, especially the thymus, undergoes age-related modifications leading to structural and functional changes in the lymphoid organs and immunocompetent cells. Nevertheless, the consequences of thymic involution in the peripheral pool of T-cells are still a matter of controversy. The control of the thymic function is very complex and involves intrathymic signals, the autonomic nervous system, and the endocrine system. Both thymocytes and thymic stromal cells express receptors for a wide range of hormones, as well as for neurotransmitters and neuropeptides, thus affecting thymocytes maturation. This review summarizes the age-dependent variations in the extrathymic components of the thymic microenvironment, i.e., vegetative nerves and hormones, and the possible effects of those changes in the immune function. Microsc. Res. Tech. 63:94,101, 2004. © 2004 Wiley-Liss, Inc. [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]


Redefining epithelial progenitor potential in the developing thymus

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2007
Simona
Abstract Cortical and medullary epithelium represent specialised cell types that play key roles in thymocyte development, including positive and negative selection of the T cell repertoire. While recent evidence shows that these epithelial lineages share a common embryonic origin, the phenotype and possible persistence of such progenitor cells in the thymus at later stages of development remain controversial. Through use of a panel of reagents including the putative progenitor marker Mts24, we set out to redefine the stages in the development of thymic epithelium. In the early embryonic day (E)12 thymus anlagen we find that almost all epithelial cells are uniformly positive for Mts24 expression. In addition, while the thymus at later stages of development was found to contain distinct Mts24+ and Mts24, epithelial subsets, thymus grafting experiments show that both Mts24+ and Mts24, epithelial subsets share the ability to form organised cortical and medullary thymic microenvironments that support T cell development, a function shown previously to be lost in the Mts24, cells by E15 when lower cell doses were used. Our data help to clarify stages in thymic epithelial development and provide important information in relation to currently used markers of epithelial progenitors. See accompanying commentary: http://dx.doi.org/10.1002/eji.200737709 [source]


Effects of aging on early B- and T-cell development

IMMUNOLOGICAL REVIEWS, Issue 1 2005
Hyeyoung Min
Summary:, Lymphocyte production in the bone marrow and the thymus is reduced during aging, but why this decline occurs has not been fully elucidated. The ability to isolate hematopoietic stem and progenitor cells using sophisticated flow cytometric strategies and to manipulate them in vitro and in vivo has provided insights into the effects of aging on primary lymphopoiesis. These analyses have showed that intrinsic changes in hematopoietic precursors that affect their proliferative potential are one factor that contributes to the age-related decline in B- and T-cell production. This and other age-related defects may be exacerbated by changes in the lymphopoietic support potential of the bone marrow and thymic microenvironments as well as by age-induced fluctuations in the production of various endocrine hormones. Particular attention with regard to the latter point has focused on changes in the production of sex steroids, growth hormone, and insulin-like growth factor-I. The present review summarizes recent studies of how age-related perturbations affect primary lymphopoiesis and highlights how the data necessitate the reevaluation of a number of existing paradigms. [source]