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Developing Thymocytes (developing + thymocyte)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

The T-cell receptor repertoire of regulatory T cells

IMMUNOLOGY, Issue 4 2008
Rafal Pacholczyk
Summary The CD4+ CD25+ regulatory population of T cells (Treg cells), which expresses the forkhead family transcription factor (Foxp3), is the key component of the peripheral tolerance mechanism that protects us from a variety of autoimmune diseases. Experimental evidence shows that Treg cells recognize a wide range of antigenic specificities with increased reactivity to self antigens, although the affinity of these interactions remains to be further defined. The Treg repertoire is highly diverse with a distinct set of T-cell receptors (TCRs), and yet is overlapping to some extent with the repertoire of conventional T cells (Tconv cells). The majority of Treg cells are generated in the thymus. However, the role of the TCR specificity in directing thymic precursors to become Treg or Tconv cells remains unclear. On the one hand, the higher self reactivity of Treg cells and utilization of different TCRs in Treg and Tconv repertoires suggest that in TCR interactions an initial decision is made about the ,suitability' of a developing thymocyte to become a Treg cell. On the other hand, as Treg cells can recognize a wide range of foreign antigens, have a diverse TCR repertoire, and show some degree of overlap with Tconv cells, the signals through the TCR may be complementary to the TCR-independent process that generates precursors of Treg cells. In this review, we discuss how different features of the Treg repertoire influence our understanding of Treg specificities and the role of self reactivity in the generation of this population. [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]

Interleukin-4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Angela M. Crawley
Abstract Signaling via the IL-7 receptor complex (IL-7R,/CD127 and IL-2R,/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2R,-sharing (,C) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated. [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]

Wnt signaling in hematopoiesis: Crucial factors for self-renewal, proliferation, and cell fate decisions

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010
Frank J.T. Staal
Abstract A large number of studies from many different laboratories have implicated the Wnt signaling pathway in regulation of hematopoiesis. However, different inducible gain- and loss-of-function approaches yielded controversial and some times contradictory results. In this prospect we will review the current ideas on Wnt signaling in hematopoiesis and early lymphopoiesis. Reviewing this large body of knowledge let us to hypothesize that different levels of activation of the pathway, dosages of Wnt signaling required and the interference by other signals in the context of Wnt activation collectively explain these controversies. Besides differences in dosage, differences in biological function of Wnt proteins in various blood cell types also is a major factor to take into account. Our own work has shown that while in the thymus Wnt signaling provides cytokine-like, proliferative stimuli to developing thymocytes, canonical Wnt signaling in HSC regulates cell fate decisions, in particular self-renewal versus differentiation. J. Cell. Biochem. 109: 844,849, 2010. © 2010 Wiley-Liss, Inc. [source]