IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)

Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system

SIGNIFICANCE OF Treg CELLS FOR ADENOSINE-MEDIATED IMMUNE SUPPRESSION IN COLORECTAL CANCER

At the present time, immunosuppressive role of extracellular adenosine in carcinogenesis is actively investigated. Colorectal cancer is one of the most common types of malignant neoplasms in Russia and worldwide, but the role of mediators of adenosine-dependent immunosuppression, such as CD39 (that hydrolyze ATP to adenosine), CD73, A2AR, is not yet clear in patients with colorectal cancer. The levels of specific mRNAs for A2AR, ectonucleotidase CD39, and CD73 genes were assayed in white blood cells of the patients with colorectal cancer. The results have shown that the CD39 mRNA content is increased in the patients with colorectal cancer in the course of the disease progression. Meanwhile, no significant difference for CD73 gene expression was found between the patients and healthy donors. Moreover, an increase in A2AR mRNA expression was noted for the patients with advanced colorectal cancer, thus presuming potential activation of adenosine-A2AR-mediated immunosuppressive mechanism. Furthermore, the CD39 expression on T cells was elevated in parallel to the cancer progression. The most significant changes in CD39 expression were observed for both T helper and Treg cell populations at the late stages of colorectal cancer. Similarly, a direct correlation was revealed between CD39 expression on CD4+CD25+CD127lo/-Treg cells, and changes of A2AR mRNA levels in leukocytes from the cancer patients

EVALUATION OF THE CONTENT OF CD4+CD25+CD127LOW REGULATORY T CELLS AND THEIR FUNCTIONAL STATUS ACCORDING TO THE EXPRESSION OF CTLA-4 AND CD39 MOLECULES IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective. To study the content of the suppressor population of regulatory T cells (Treg) according to the expression of CD4, CD25, CD127 molecules, as well as the expression of two functional molecules (CTLA-4 and CD39) in patients with rheumatoid arthritis (RA). Material and methods. 16 samples of peripheral blood of RA patients and 10 blood samples of healthy donors were analyzed. All patients received disease-modifying anti-rheumatic drugs. The expression level of all studied molecules was assessed by flow cytofluorometry. Results. The content of T-helpers in peripheral blood of RA patients was 36.3 ± 7.1% of the total number of lympho- cytes and was lower than that in the control (43.8 ± 6.2%, p<0.05). The number of activated CD4+CD25+ T cells in these patients increased twofold (RA 23.7 ± 9.8%, control 11.1 ± 2.0% of the number of CD4+ T cells, p<0.05). The relative amount of CD4+CD25high (RA 2.7 ± 1.0%, control 1.5 ± 0.8%) and CD4+CD25highCD127low/- (RA 2.5 ± 1.0%, control 1.6 ± 0.9% of CD4+ T cells) Treg cells in RA patients was significantly higher than that in healthy individuals (p<0.05). The expression of the CTLA-4 negative regulatory molecule and CD39 ectonucleotidase by Treg cells of RA patients did not differ from the control. Conclusion. The study demonstrated that RA is characterized by an increased content of Treg cells of CD4+CD25high and CD4+CD25highCD127low phenotypes rather than CD4+CD25+CD127low, as well as by the control-like expression of CTLA-4 and CD39 functional molecules by Treg cells

Matrisome Transcriptome Dynamics during Tissue Aging

The extracellular matrix (ECM) is a complex three-dimensional network of macromolecules that provides structural support for the cells and plays a significant role in tissue homeostasis and repair. Growing evidence indicates that dysregulation of ECM remodeling contributes to various pathological conditions in the body, including age-associated diseases. In this work, gene expression data of normal human tissues obtained from the Genotype-Tissue Expression project, as well as data from MatrisomeDB 2.0, the ECM-protein knowledge database, are used to estimate the age-dependent matrisome transcriptome dynamics in the blood, heart, brain, liver, kidneys, lungs, and muscle. Differential gene expression (DE) analysis revealed dozens of matrisome genes encoding both structural elements of the ECM and ECM-associated proteins, which had a tissue-specific expression profile with age. Among common DE genes that changed expression with age in at least three tissues, COL18A1, MFAP1, IGFBP7, AEBP1, LTBP2, LTBP4, LG14, EFEMP1, PRELP, BGN, FAM20B, CTSC, CTSS, and CLEC2B were observed. The findings of the study also reveal that there are sex-specific alterations during aging in the matrisome gene expression. Taken together, the results obtained in this work may help in understanding the role of the ECM in tissue aging and might prove valuable for the future development of the field of ECM research in general

Epigenetics in the pathogenesis of RA

Epigenetic modifications can stably alter gene expression and have been shown to be important in the maintenance of cell type-specific functions as well as in cell differentiation, e.g., in T and B cell maturation. In RA, alterations in DNA methylation, histone modifications, and microRNA expression have been found in immune as well as in stromal cells. These changes in the epigenome in RA patients influence key inflammatory and matrix-degrading pathways and are suspected to play a major role in the pathogenesis of RA. In this manuscript, we explain the basic mechanisms of epigenetics, review studies that analyzed epigenetic changes in RA, and assess their potential as therapeutic targets