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Lipid Signaling in T Cell Development and Function
Lipids are best known as energy storing molecules and core-components of cellular membranes, but can also act as mediators of cellular signaling. This is most prominently illustrated by the paramount importance of the phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K) signaling pathways in many cells, including T cells and cancer cells. Both of these enzymes use the lipid phosphatidylinositol(4,5)bisphosphate (PIP2) as their substrate. PLCs produce the lipid product diacylglycerol (DAG) and soluble inositol(1,4,5)trisphosphate (IP3). DAG acts as a membrane tether for protein kinase C and RasGRP proteins. IP3 is released into the cytosol and controls calcium release from internal stor...
Investigating and harnessing T-cell functions with engineered immune receptors and their ligands
T-cells are an essential component of the immune system that provide protection against pathogen infections and cancer and are involved in the aetiology of numerous autoimmune and autoinflammatory pathologies. Their importance in disease, the relative ease to isolate, expand and manipulate them ex vivo have put T-cells at the forefront of basic and translational research in immunology. Decades of study have shed some light on the unique way T-cells integrate extrinsic environmental cues influencing an activation program triggered by interactions between peptide-MHC complexes and the antigen-recognition machinery constituted of clonally distributed T-cell receptors and their co-receptor CD4 o...
Regulation of immune system cell functions by protein kinase C
Members of the protein kinase C (PKC) family of Ser/Thr kinases are encoded by nine distinct but closely related genes, which give rise to more than 12 different protein isoforms via a mechanism of alternative RNA splicing. Most PKC proteins are ubiquitously expressed and participate in a plethora of functions in most cell types. A majority of PKC isoforms is also expressed in cells of the immune system in which they are involved in signal transduction downstream of a range of surface receptors, including the antigen receptors on T and B lymphocytes. PKC proteins are central to signal initiation and propagation, and to the regulation of processes leading to immune cell proliferation, differe...
The Molecular Mechanisms of Regulatory T cell Immunosuppression
Ever since Regulatory T cells (T-Regs) were first defined as peripheral CD4+ T cells that express the interleukin-2 (IL-2) receptor alpha chain (IL-2Ra), there have been intensive efforts to determine the molecular mechanisms whereby this minor subset of CD4+ T cells (~ 5-10%) nonspecifically suppresses all potential effector T cells, whether reactive to self or non-self antigens. Multiple possible molecular mechanisms have been implicated, including the scavenging of IL-2 via the expression of high densities of IL-2Rs, the inhibition of antigen presentation via CTLA-4 molecules leading to decreased IL-2 production, the activation of intracellular cAMP thereby suppressing both IL-2 productio...
T cell specificity and Cross-reactivity – Implications in Physiology and Pathology
Conventional CD8+ and CD4+ T cells recognize antigens, presented by antigen-presenting cells in the form of short peptides loaded onto major histocompatibility complex (MHC) class I and class II molecules, through their T cell receptor (TCR). Somatic gene rearrangement of the TCR locus and randomization of TCR hyper-variable regions generate the marked diversity of TCRs. Once assembled, the heterodimeric TCR confers specificity to naïve T cells. The naïve T cell repertoire of an individual is established by selection processes in the thymus and cannot be broadened upon antigen recognition by additional somatic mutations. In humans, the estimated number of distinct TCRs in the naïve T cell...
The T-Cell Receptors
The importance of thymus-dependent cells, or T cells, in the generation of a successful immune response was first realized in the early sixties. In the follow ing two decades, a succession of elegant experiments established the antigen specificity of T cells and their ability to perform both as regulatory and effector cells. T cells were shown to be essential in most immune reactions, playing a crucial role in augmenting the activity of effector T and B cells against 'foreign' antigen, as well as in the suppression of effector activity against self antigens. The means by which T cells differentiate 'foreign' from 'self' antigens is based on their recognition of antigen almost exclusively in ...
Immune system modeling and analysis
The rapid development of new methods for immunological data collection – from multicolor flow cytometry, through single-cell imaging, to deep sequencing – presents us now, for the first time, with the ability to analyze and compare large amounts of immunological data in health, aging and disease. The exponential growth of these datasets, however, challenges the theoretical immunology community to develop methods for data organization and analysis. Furthermore, the need to test hypotheses regarding immune function, and generate predictions regarding the outcomes of medical interventions, necessitates the development of mathematical and computational models covering processes on multiple s...
Cellular Therapy Of Cancer: Development Of Gene Therapy Based Approaches
Cancer research has progressed enormously in recent years. This review volume will address recent findings in the area of T-cell therapy for cancer, including use of tumour infiltrating lymphocytes (TILs) as a therapy for melanoma, choice of target antigens, advances in engineered receptors, methods of gene transfer to T cells, review of cell processing methods and clinical trial design. Written by leadings scientists in the field, this up-to-date review on cancer research will be an important reference source to the researchers and healthcare professionals in the field.
