The review describes advances in understanding the role of the CD3 delta subunit in human T-cell development as deduced from a recently described human immunodeficiency. The review also compares CD3 delta deficiency with other human CD3 subunit deficiencies and with corresponding animal models.
In describing CD3 delta deficiency in humans this review shows that patients with profound T-cell depletion, who present at 2-3 months with severe viral infection, lack CD3 delta as a result of a mutation in the extracellular domain of this gene. The genetic aberration was discovered by comparing patients' and normal thymocytes, using mass gene screening with the microarray technique. In humans the absence of CD3 delta results in a complete arrest in thymocyte development at the stage of double negative to double positive transition and the development of gamma delta T-cell receptor-positive T cells is also impaired.
Unlike patients with CD3 gamma or CD3 epsilon deficiency who have a milder condition, patients with CD3 delta deficiency present with severe lethal susceptibility to infections during early infancy. As expected, this profound immunodeficiency was cured with an allogenic bone marrow transplantation. In contrast to murine CD3 (-/) delta, which retains a normal gamma delta T-cell receptor-positive T-cell population and only partly affects the developmental transition of double positive to single positive thymocytes, CD3 delta in humans appears to be more critically required for the development of both alpha beta and gamma delta T-cell receptor-positive T-cell lineages. The studies also show for the first time that comparing relevant patients' with normal tissue using microarray technology can aid in the discovery of the genetic basis of inherited disorders.
[Show abstract][Hide abstract] ABSTRACT: Receptor-mediated transmembrane signaling plays an important role in health and disease. Recent significant advances in our understanding of the molecular mechanisms linking ligand binding to receptor activation revealed previously unrecognized striking similarities in the basic structural principles of function of numerous cell surface receptors. In this work, I demonstrate that the Signaling Chain Homooligomerization (SCHOOL)-based mechanism represents a general biological mechanism of transmembrane signal transduction mediated by a variety of functionally unrelated single- and multichain activating receptors. within the SCHOOL platform, ligand binding-induced receptor clustering is translated across the membrane into protein oligomerization in cytoplasmic milieu. This platform resolves a long-standing puzzle in transmembrane signal transduction and reveals the major driving forces coupling recognition and activation functions at the level of protein-protein interactions-biochemical processes that can be influenced and controlled. The basic principles of transmembrane signaling learned from the SCHOOL model can be used in different fields of immunology, virology, molecular and cell biology and others to describe, explain and predict various phenomena and processes mediated by a variety of functionally diverse and unrelated receptors. Beyond providing novel perspectives for fundamental research, the platform opens new avenues for drug discovery and development.
Self/Nonself - Immune Recognition and Signaling 01/2010; 1(1):4-39. DOI:10.4161/self.1.1.10832
[Show abstract][Hide abstract] ABSTRACT: Background Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. Methodology/Principal Findings We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5). Conclusions/Significance Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation. Yes Yes
[Show abstract][Hide abstract] ABSTRACT: Receptor-mediated signaling plays an important role in health and disease. Recent reports have revealed that many proteins that do not adopt globular structures under native conditions, thus termed intrinsically disordered, are involved in cell signaling. Intriguingly, physiologically relevant oligomerization of intrinsically disordered proteins has been recently observed and shown to exhibit unique biophysical characteristics. On the other hand, ligand-induced or -tuned receptor oligomerization is known to be a general feature of various cell surface receptors and to play a crucial role in signal transduction. In this work, I summarize several distinct features of protein disorder that are especially important as related to signal transduction. Further, I suggest signaling-related functional connections between intrinsic disorder, receptor and protein oligomericity and hypothesize that receptor oligomerization induced or tuned upon ligand binding outside the cell is translated across the membrane into protein oligomerization inside the cell, thus providing a general platform for receptor-mediated signaling. This structures our current multidisciplinary knowledge and views of the mechanisms governing the coupling of recognition to signal transduction and cell response. Importantly, this approach not only reveals previously unrecognized striking similarities in the basic mechanistic principles of function of numerous functionally diverse and unrelated surface membrane receptors, but also suggests the similarity between therapeutic targets, thus opening new horizons for both fundamental and clinically relevant studies.
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