DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis (original) (raw)
Related papers
T CELL AGING IN RHEUMATOID ARTHRITIS
Review Paper, 2022
With the progression of aging, the immune system and the tendency for abnormal immunological changes are common. Individuals over the age of 50 years are susceptible to infectious diseases as well as inflammation and immune-mediated tissue damage. Aging is the main cause of disease pathology and death, continuously enhancing the risk of cardiovascular disease, malignancy, and infectious diseases. One of the important causes is higher susceptibility to autoimmune diseases like rheumatoid arthritis and other immunodeficiency syndromes. Inflammation is common in age-related pathologies. In immune cells, T lymphocytes have an extensive life cycle and show a robust copying force, constructing them sensitive to ageing-associated pathologies. In dysfunctional ageing of T-cells, protection of T-cell function and cells capable of promoting inflammation are abundant. Rheumatoid arthritis is a long-lasting autoimmune disease that mainly affects the joints. Though RA develops at an early age, the frequency of developing RA increases with the increase in age. It is also seen that RA may develop as a result of premature ageing (immunosenescence) of the immune system. In RA, T-cell ageing occurs prematurely, but the mechanism involved and their role in tissue damage is still uncertain. T-cell ageing and its effects on rheumatoid arthritis are discussed here, as well as how T-cells participate in tissue damage, acute and chronic inflammation, and the ageing process. Also review the DNA damage in response to T-cell aging, telomeric ends shortening during RA and immunosenescence, and Tcells in RA.
Immunology Letters, 2005
Although telomerase activity is important in normal immune function, it is unclear whether telomerase or telomerase (dys)regulation plays a role in the pathogenic immune response in autoimmune diseases like rheumatoid arthritis (RA). In this study we evaluated the dynamics of the activation-induced human Telomerase Reverse Transcriptase (hTERT) response in RA patients and non-RA controls. The expression of the catalytic subunit of telomerase, hTERT, was measured in PBMC of RA patients and controls after in vitro stimulation with anti-CD3 monoclonal antibody (mAb) using real-time PCR. Anti-CD3 mAb stimulation induced activation and proliferation of the T cells in all populations studied. In early RA patients with a disease duration of less than a year, the activation-induced hTERT mRNA levels were found to be reduced as compared to healthy controls (HC). Chronic RA patients, with a disease duration of more than one year, did not show these impaired hTERT mRNA levels after stimulation with anti-CD3 mAb. Decreased hTERT mRNA levels were also found in multiple sclerosis patients and patients suffering from flu-like symptoms, indicating that these deviations are not disease-specific. The impaired activation-induced hTERT response in PBMC may be a general response of the immune cells in cases of acute or chronic immuneactivation, presumably to control unwanted clonal expansions and to maintain the diversity of the TCR repertoire. Our results also indicate that clonal T cell expansions, described in RA, are probably not mediated by an elevated potency to express hTERT.
Reversible Senescence in Human CD4+CD45RA+CD27- Memory T Cells
The Journal of Immunology, 2011
Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4 + effector memory (EM) T cells (CD27 2 CD45RA 2 ) and also EM T cells that re-express CD45RA (CD27 2 CD45RA + ; EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear gH2AX after TCR activation. A paradoxical observation was that although CD4 + EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27 + CD45RA 2 ) and EM (CD27 2 CD45RA 2 ) CD4 + T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-a inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4 + EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4 + T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4 + EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4 + T cells. In particular, CD4 + EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.
Frontiers in Immunology, 2019
Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function, and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found that levels of hTERT mRNA and telomerase activity had an ordered decrease from naïve (T N) to central memory (T CM) to effector memory (T EM) cells and were higher in CD4 + than their corresponding CD8 + subsets. This differentiation-related reduction of hTERT mRNA and telomerase activity was preserved after activation. Furthermore, the levels of hTERT mRNA and telomerase activity were positively correlated with the degree of activation-induced proliferation and survival of T cells in vitro. Partial knockdown of hTERT by an anti-sense oligo in naïve CD4 + cells led to a modest but significant reduction of cell proliferation. Finally, we found that activation-induced levels of telomerase activity in CD4 + T N and T CM cells were significantly lower in old than in young subjects. These findings reveal that hTERT/telomerase expression progressively declines during T cell differentiation and age-associated reduction of activation-induced expression of hTERT/telomerase mainly affects naïve CD4 + T cells and suggest that enhancing telomerase activity could be a strategy to improve T cell function in the elderly.
Telomerase levels control the lifespan of human T lymphocytes
Blood, 2003
The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of human T lymphocytes. Although telomerase is transiently expressed in T lymphocytes upon activation, it is insufficient to confer immortality. We have previously shown that immortalization of human CD8 ؉ T lymphocytes can be achieved by ectopic expression of the human telomerase reverse transcriptase (hTERT) gene, which encodes for the catalytic component of the telomerase complex. To study the role of endogenous hTERT in the lifespan of human T cells, we blocked endogenous hTERT expression by ectopic expression of dominant-negative (DN) hTERT. Cells expressing DN-hTERT had a decreased lifespan and showed cytogenetic abnormalities, including chromosome ends without detectable telomeric DNA as well as chromosome fusions. These results indicate that while endogenous hTERT cannot prevent overall telomere shortening, it has a major influence on the longevity of human T cells. Furthermore, we show that up-regulation of hTERT in T cells upon activation decreases over time in culture. Long-term-cultured T cells also show a decreased expression of c-myc upon activation, resulting in less c-mycinduced transcription of hTERT. Moreover, memory T cells, which have expanded in vivo upon antigen encounter, expressed a lower level of hTERT upon activation than naive cells from the same donor. The observed inverse correlation between telomerase levels and replicative history suggests that telomerase levels in T cells are limiting and increasingly insufficient to sustain their proliferation. (Blood. 2003;102:849-857)
The telomere/telomerase system in autoimmune and systemic immune-mediated diseases
Autoimmunity Reviews, 2010
Telomeres are specialized nucleoproteic structures that cap and protect the ends of chromosomes. They can be elongated by the telomerase enzyme, but in telomerase negative cells, telomeres shorten after each cellular division because of the end replicating problem. This phenomenon leads ultimately to cellular senescence, conferring to the telomeres a role of biological clock. Oxidative stress, inflammation and increased cell renewal are supplementary environmental factors that accelerate age-related telomere shortening. Similar to other types of DNA damage, very short/dysfunctional telomeres activate a DNA response pathway leading to different outcomes: DNA repair, cell senescence or apoptosis. During the last 10 years, studies on the telomere/telomerase system in autoimmune and/or systemic immune-mediated diseases have revealed its involvement in relevant physiopathological processes. Here, we present a literature review of telomere and telomerase homeostasis in systemic inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis and granulomatous diseases. The available data indicate that both telomerase activity and telomere length are modified in various systemic immune-mediated diseases and appear to be connected with premature immunosenescence. Studies on the telomere/ telomerase system open new research avenues for the basic understanding and for therapeutic approaches of these pathologies.
Telomere uncapping during in vitro T-lymphocyte senescence
Aging Cell, 2009
As previously reported, we showed that, during lymphocyte long-term culture and repeated stimulations, the appearance of senescent cells is associated with telomere shortening and a progressive drop in telomerase activity. We further showed that this shortening preferentially occured at long telomeres and was interrupted at each stimulation by a transitory increase in telomere length. In agreement with the fact that telomere uncapping triggers lymphocyte senescence, we observed an increase in γ γ γ γ -H2AX and 53BP1 foci as well as in the percentage of cells exhibiting DNA damage foci in telomeres. Such a DNA damage response may be related to the continuous increase of p16 ink4a upon cell stimulation and cell aging. Remarkably, at each stimulation, the expression of shelterin genes, such as hTRF1 , hTANK1 , hTIN2 , hPOT1 and hRAP1 , was decreased. We propose that telomere dysfunction during lymphocyte senescence caused by iterative stimulations does not only result from an excessive telomere shortening, but also from a decrease in shelterin content. These observations may be relevant for T-cell biology and aging.