Stochastics of Cellular Differentiation Explained by Epigenetics: The Case of T-Cell Differentiation and Functional Plasticity.

Epigenetic marks including histone modifications and DNA methylation are associated with the regulation of gene expression and activity. In addition, an increasing number of non-coding RNAs with regulatory activity on gene expression have been identified. Alongside, technological advancements allow for the analysis of these mechanisms with high resolution up to the single-cell level. For instance, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) simultaneously probes for chromatin accessibility and nucleosome positioning. Thus, it provides information on two levels of epigenetic regulation. Development and differentiation of T cells into functional subset cells including memory T cells are dynamic processes driven by environmental signals. Here, we briefly review the current knowledge of how epigenetic regulation contributes to subset specification, differentiation and memory development in T cells. Specifically, we focus on epigenetic mechanisms differentially active in the two distinct T cell populations expressing αß or γδ T cell receptors. We also discuss examples of epigenetic alterations of T cells in autoimmune diseases. DNA methylation and histone acetylation are subject to modification by several classes of 'epigenetic modifiers', some of which are in clinical use or in preclinical development. Therefore, we address the impact of some epigenetic modifiers on T-cell activation and differentiation, and discuss possible synergies with T cell-based immunotherapeutic strategies.

Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications.

The activating natural killer group 2 member D (NKG2D) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG2D comprise two groups of MHC class I-related molecules, the MHC class I chain-related proteins A and B (MICA/B) and 6 UL16-binding proteins (ULBP1-6). While NKG2D ligands are absent from most normal cells, expression is induced upon stress and malignant transformation. In fact, most solid tumours and leukaemia/lymphomas constitutively express at least one NKG2D ligand and thereby are susceptible to NKG2D-dependent immunosurveillance. However, soluble NKG2D ligands are released from tumour cells and can down-modulate NKG2D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG2D ligands in the serum correlate with tumour progression. NKG2D ligands can be proteolytically shed from the cell surface or liberated from the membrane by phospholipase C in the case of glycosylphosphatidylinositol (GPI)-anchored molecules. Moreover, NKG2D ligands can be secreted in exosomal microvesicles together with other tumour-derived molecules. Depending on the specific tumour/immune cell setting, these various forms of soluble and/or exosome-bound NKG2D ligands can exert multiple effects on NKG2D/NKG2D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG2D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome-secreted NKG2D ligands for immunosurveillance.

[Calorimetry of chromatin and DNA from ascitic cells of C3HA mice in the presence of copper ions]. / Kalorimetriia khromatina i DNK astsitnykh kletok myshei linii C3HA v prisutstvii ionov medi.

The process of chromatin denaturation in the composition of C3HA line mice ascites cells was investigated by the method of scanning microcalorimetry. It is shown that copper ions injected into ascites tumour are inculcated in DNA double helix and injure it, and this caused disorder of high ordered chromatin structure.

[Microcalorimetric study of intact nucleoproteins]. / Mikrokalorimetricheskoe issledovanie intaktnykh nukleoproteidov.

It has been shown that melting of native chromatin complex in tissues and cells is a one stage process with transition parameters Tm = 82 +/- 1 degrees C, delta Tm = 6 degrees C and Qm = (24 +/- 3) cal/g DNA. A conclusion is made that the difference in melting temperatures of chromatin complex and DNA, which is 12 cal/g DNA, corresponds to the melting of secondary and tertiary structures of chromatin. It is shown the destruction of significant part of the secondary and tertiary structures of chromatin by the chromatin complex isolation from tissues and cells.