Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy

Background The thymic microenvironment is mainly comprised of thymic epithelial cells, the cytokines, exosomes, surface molecules, and hormones from the cells, and plays a vital role in the development, differentiation, maturation and homeostasis of T lymphocytes. However, the thymus begins to degenerate as early as the second year of life and continues through aging in human beings, leading to a decreased output of naïve T cells, the limited TCR diversity and an expansion of monoclonal memory T cells in the periphery organs. These alternations will reduce the adaptive immune response to tumors and emerging infectious diseases, such as COVID-19, also it is easier to suffer from autoimmune diseases in older people. In the context of global aging, it is important to investigate and clarify the causes and mechanisms of thymus involution. Main body Epigenetics include histone modification, DNA methylation, non-coding RNA effects, and chromatin remodeling. In this review, we discuss how senescent thymic epithelial cells determine and control age-related thymic atrophy, how this process is altered by epigenetic modification. How the thymus adipose influences the dysfunctions of the thymic epithelial cells, and the prospects of targeting thymic epithelial cells for the treatment of thymus atrophy. Conclusion Epigenetic modifications are emerging as key regulators in governing the development and senescence of thymic epithelial cells. It is beneficial to re-establish effective thymopoiesis, identify the potential therapeutic strategy and rejuvenate the immune function in the elderly.

The BMMSCs Derived From Juvenile Macaques Have the Ability to Promote Thymus Regeneration in Aged Macaques

BackgroundThe thymus gland is an important central immune organ in the human body and plays an indispensable role in the immune system. Aging thymic atrophy is critical factors leading to immune function decline and senile debilitation in aged people. Immune function decline is one of the important mechanisms of aging. Some research reports indicated that Stem cell therapy have the ability to promote tissue regeneration，but reverse thymus atrophy or promote atrophy thymus regenerate by stem cells need to be confirmed further. MethodsThe elderly macaque models were systematic screened and the thymus structure and function were evaluated by imaging and histopathology methods. The juvenile BMMSCs were injected into macaque models body by intravenous infusion. The effects of thymus tissue structure and expression of related factors were investigated by using imaging, histopathology,cell and molecule observation and measurement techniques. To explore the mechanism of juvenile BMMSC on thymus atrophy in aging rhesus macaques, the gene transcription profile of thymus tissue were sequencing and analyzed by bioinformatic methods. .ResultsThrough PET-CT observation, the thymus tissue density gradually increased after treatment, CT value gradually increased, SUVmax >1;The percentage of CD3+T cells in peripheral blood increased first and then decreased, CD3+CD4+T cells increased slowly, and CD3+CD8+T cells increased first, then decreased and then increased. By detecting Tregs in peripheral blood, the percentage of Tregs in peripheral blood showed a trend of decreasing first and then increasing after treatment (P< 0.05).The levels of thymosin α and thymosin II in peripheral blood were analyzed by ELISA method. It was found that thymosin α was firstly increased and then decreased after BMSC infusion, and the levels of thymosin Ⅱ were firstly increased and then decreased.The area of thymus parenchyma increased, and the boundary between skin and medulla appeared. Some thymus tissues were regenerated and changed to normal structure.The cortical and medullary junction structure and dense thymus structure gradually appeared in the elderly treatment group.The degree of thymus tissue fibrosis was reduced, and the deposition of collagen fiber was reduced. Apoptosis cells decreased significantly in the elderly treatment group compared with the elderly group. BMMSCs inhibited the expression of genes related to aging and apoptosis.ConclusionTransplantation BMMSC derived from juvenile macaques can poromote thymus regeneration, reverse thymus atrophy by regulating gene transcription profiles in aged macaques.

Up-Regulation of Immune Checkpoints in the Thymus of PRRSV-1-Infected Piglets in a Virulence-Dependent Fashion

Virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains, such as the Lena strain, have demonstrated a higher thymus tropism than low virulent strains. Virulent PRRSV strains lead to severe thymus atrophy, which could be related to marked immune dysregulation. Impairment of T-cell functions through immune checkpoints has been postulated as a strategy executed by PRRSV to subvert the immune response, however, its role in the thymus, a primary lymphoid organ, has not been studied yet. Therefore, the goal of this study was to evaluate the expression of selected immune checkpoints (PD1/PDL1, CTLA4, TIM3, LAG3, CD200R1 and IDO1) in the thymus of piglets infected with two different PRRSV-1 strains. Thymus samples from piglets infected with the low virulent 3249 strain, the virulent Lena strain and mock-infected were collected at 1, 3, 6, 8 and 13 days post-infection (dpi) to analyze PRRSV viral load, relative quantification and immunohistochemical staining of immune checkpoints. PD1/PDL1, CTLA4, TIM3, LAG3 and IDO1 immune checkpoints were significantly up-regulated in the thymus of PRRSV infected piglets, especially in those infected with the virulent Lena strain from 6 dpi onwards. This up-regulation was associated with disease progression, high viral load and cell death. Co-expression of these molecules can affect T-cell development, maturation and selection, negatively regulating the host immune response against PRRSV.

Thymus size and its correlates among children admitted with severe acute malnutrition: a cross-sectional study in Uganda

Background Malnutrition continues to be a major cause of mortality and morbidity among children in resource limited settings. Children with severe acute malnutrition (SAM) experience severe thymus atrophy, possibly reflecting poor immune function. This immune dysfunction is responsible for the severe infections they experience which lead to mortality. Since their immune dysfunction is not fully understood and there has been a lapse in research in this field, more research is needed. Knowing the correlates of thymus size may help clinicians identify those with more severe atrophy who might have more severe immune impairment. We aimed to describe thymus size and its correlates at admission among children hospitalized with SAM. Methods This cross-sectional study involved children 6-59 months admitted with complicated SAM in Mulago National Referral Hospital. Well-nourished children from same communities were used as a community reference group for thymus size. At admission, thymus size was measured by ultrasound scan. Demographic, clinical and laboratory variables were identified at admission. A linear regression model was used to determine correlates of thymus size among children with SAM. Results Among 388 children with SAM, the mean age was 17±8.5 months and 58% were boys. The mean thymus size was 3.14 (95% CI 2.9; 3.4) cm2 lower than that of the 27 healthy community reference children (1.06 vs 4.2 cm2, p<0.001) when controlled for age. Thymus size positively correlated with current breastfeeding (0.14, 95% CI 0.01, 0.26), anthropometric measurements at admission (weight, length, mid-upper-arm circumference, weight-for-height Z scores and length-for-age Z scores) and suspected tuberculosis (0.12, 95% CI 0.01; 0.22). Thymus size negatively correlated with > 2 weeks duration of sickness (-0.10; 95% CI -0.19; -0.01). Conclusion The thymus is indeed a barometer for nutrition since all anthropometric measurements and breastfeeding were associated with bigger thymus. The immune benefits of breastfeeding among children with SAM is underscored. Children with longer duration of illness had a smaller thymus gland indicating that infections have a role in the cause or consequence of thymus atrophy.

Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

Activation of the aryl hydrocarbon receptor (AHR) by the environmental toxin dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) causes diverse toxicities, including thymus atrophy and hepatosteatosis. The mechanisms by which AHR activation by TCDD leads to these toxicities are not fully understood. Here we studied the effects of TCDD on a major energy pathway, glycolysis, using the chick embryo close to hatching, a well-established model for studying dioxin toxicity. We showed that 24 hr of TCDD treatment causes changes in glycolysis in both thymus and liver. In thymus glands, TCDD decreased mRNAs for glycolytic genes and glucose transporters, glycolytic indices and levels of IL7 mRNA, phosphorylated AKT (pAKT) and HIF1A, stimulators of glycolysis and promoters of survival and proliferation of thymic lymphocytes. In contrast, in liver, TCDD increased mRNA levels for glycolytic genes and glucose transporters, glycolytic endpoints and pAKT levels. Similarly, increases by TCDD in mRNA levels for glycolytic genes and glucose transporters in human primary hepatocytes showed that effects in chick embryo liver pertain also to human cells. Treatment with the glycolytic inhibitor 2-deoxy-d-glucose exacerbated the effects on thymus atrophy by TCDD, supporting a role for decreased glycolysis in thymus atrophy by TCDD, but did not prevent hepatosteatosis. NAD+ precursors abolished TCDD effects on glycolytic endpoints in both thymus and liver. In summary, we report here that dioxin disrupts glycolysis mediated energy metabolism in both thymus and liver, and that it does so in opposite ways, decreasing it in the thymus and increasing it in the liver. Further, the findings support NAD+ boosting as a strategy against metabolic effects of environmental pollutants such as dioxins.

Changes in oxidation-antioxidation function on the thymus of chickens infected with reticuloendotheliosis virus

Background Reticuloendotheliosis virus (REV) is a retrovirus that causes severe immunosuppression in poultry. Animals grow slowly under conditions of oxidative stress. In addition, long-term oxidative stress can impair immune function, as well as accelerate aging and death. This study aimed to elucidate the pathogenesis of REV from the perspective of changes in oxidative-antioxidative function following REV infection. Methods A total of 80 one-day-old specific pathogen free (SPF) chickens were randomly divided into a control group (Group C) and an REV-infected group (Group I). The chickens in Group I received intraperitoneal injections of REV with 104.62/0.1 mL TCID50. Thymus was collected on day 1, 3, 7, 14, 21, 28, 35, and 49 for histopathology and assessed the status of oxidative stress. Results In chickens infected with REV, the levels of H2O2 and MDA in the thymus increased, the levels of TAC, SOD, CAT, and GPx1 decreased, and there was a reduction in CAT and Gpx1 mRNA expression compared with the control group. The thymus index was also significantly reduced. Morphological analysis showed that REV infection caused an increase in the thymic reticular endothelial cells, inflammatory cell infiltration, mitochondrial swelling, and nuclear damage. Conclusions These results indicate that an increase in oxidative stress enhanced lipid peroxidation, markedly decreased antioxidant function, caused thymus atrophy, and immunosuppression in REV-infected chickens.

Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T cell development

ABSTRACTFoxp3+regulatory T (Treg) cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+Foxp3-or CD25-Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.

Changes in mouse thymus after exposure to tube-restraint stress

The thymus is the primary lymphoid organ involved in the regulation of the immune and endocrine systems. It is particularly sensitive to various types of stress, which induce its atrophy. This study deals with the effect of repeated restraint stress on the weight, proliferation and apoptosis of the thymus in mice. During restraint, the animals were placed in 50-mL conical plastic tubes for 2 h every day for either 10 or 20 consecutive days. A significant reduction in thymus weight along with decreased cellularity and pronounced atrophy of the cortical part of the thymus was observed in animals exposed to repeated tube-restraint stress for 10 and 20 consecutive days. The observed changes in the thymus were the same, regardless of the number of days of exposure to stress. These findings provide a more comprehensive view of repeated tube-restraint, with special emphasis on its duration on stress-induced thymus atrophy. The presented findings could serve as a basis for further studies aimed at identifying the mechanisms responsible for the adaptive response of the thymus after repeated exposure to stress.