scholarly journals Age-Related Changes in Thymic Central Tolerance

2021 ◽  
Vol 12 ◽  
Author(s):  
Jayashree Srinivasan ◽  
Jessica N. Lancaster ◽  
Nandini Singarapu ◽  
Laura P. Hale ◽  
Lauren I. R. Ehrlich ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Adult Transition ◽  
Treg Function ◽  
Age Related ◽  
And Function ◽  
Antigen Presenting ◽  
Age Related Changes

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.

scholarly journals P03.07 Analysis of scRNAseq from the human thymus nominates genes potentially missing from central tolerance of cytotoxic T cells

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A15.2-A16
Author(s):  
L Blumenberg ◽  
G Atwal ◽  
A Dhanik
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
Cytotoxic T Cells ◽  
Peripheral Tolerance ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Human Thymus ◽  
Part Time ◽  
Self Antigens

BackgroundDuring thymic development, cytotoxic T cells that can bind to and attack self antigens undergo negative selection thus preventing damage to the self tissues. The sparse medullar thymic epithelial cells (mTECs) present in the thymus are responsible for presenting self antigens to T cells so that they can trigger apoptosis or differentiation into non-cytotoxic lineages if they bind too strongly.Materials and MethodsUnderstanding gene expression in mTECs is essential for understanding the shape of the human T cell receptor repertoire, which is key for current and emerging cancer immunotherapies. Recent availability of human thymus single cell RNAseq (scRNAseq) data provides an extremely high-resolution view into the pattern of expression within this critical cell type. To determine which epitopes have had to opportunity to be presented during T cell negative selection, we analyzed the human thymus scRNAseq dataset to establish which genes are expressed in mTECs and therefore subject to central tolerance.ResultsThe coverage of the whole transcriptome of a particular cell is generally sparse. It is therefore difficult to understand basic features of individual cells or cell types such as how many genes are expressed. We used cell- and read-level subsampling to estimate whether a sufficient number of cells and reads had been captured to support categorizing a gene as non-expressed in mTECs. We also examined the expression of the genes not expressed in mTECs in other healthy tissues, and found their expression was almost exclusively restricted to the testis (an immune-privileged site) and the liver (a site of peripheral tolerance)ConclusionsAltogether, these analyses establish a strategy for determining if a data set has sufficient depth to estimate the total number of genes expressed and secondly define a key list of genes that are not expressed during central tolerization of T cells, which represent a compelling list of possible cancer immunotherapy targets.Disclosure InformationL. Blumenberg: A. Employment (full or part-time); Significant; Regeneron Pharmaceuticals. G. Atwal: A. Employment (full or part-time); Significant; Regeneron Pharmaceuticals. A. Dhanik: A. Employment (full or part-time); Significant; Regeneron Pharmaceuticals.

scholarly journals The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Izumi Ohigashi ◽  
Melina Frantzeskakis ◽  
Alison Jacques ◽  
Sayumi Fujimori ◽  
Aya Ushio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Negative Selection ◽  
Cd8 T Cell ◽  
Thymic Epithelial Cells ◽  
Tcr Repertoire ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells ◽  
Antigen Presenting

The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus.

scholarly journals Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging

2020 ◽  
Author(s):  
Jiyoung Oh ◽  
Weikan Wang ◽  
Rachel Thomas ◽  
Dong-Ming Su
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Negative Selection ◽  
De Novo ◽  
The Elderly ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Embryonic Fibroblasts ◽  
Central Tolerance ◽  
Age Related

AbstractAge-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly.Graphical AbstractA novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.

scholarly journals Dormant pathogenic CD4+ T cells are prevalent in the peripheral repertoire of healthy mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna Cebula ◽  
Michal Kuczma ◽  
Edyta Szurek ◽  
Maciej Pietrzak ◽  
Natasha Savage ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Receptors ◽  
Negative Selection ◽  
Regulatory Cells ◽  
Central Tolerance ◽  
Therapeutic Advantage ◽  
Autoreactive T Cell ◽  
Peptide Complexes ◽  
Self Peptides

Abstract Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3− T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3− cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including self-peptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage.

scholarly journals Physical activity in elderly

2015 ◽  
Vol 25 (4) ◽  
pp. 249 ◽  
Author(s):  
Jan Cvecka ◽  
Veronika Tirpakova ◽  
Milan Sedliak ◽  
Helmut Kern ◽  
Winfried Mayr ◽  
...  
Keyword(s):  
Physical Activity ◽  
Electrical Stimulation ◽  
Muscle Mass ◽  
Irreversible Process ◽  
Significant Decline ◽  
Positive Effects ◽  
Age Related ◽  
And Performance ◽  
And Function ◽  
Age Related Changes

Aging is a multifactorial irreversible process associated with significant decline in muscle mass and neuromuscular functions. One of the most efficient methods to counteract age-related changes in muscle mass and function is physical exercise. An alternative effective intervention to improve muscle structure and performance is electrical stimulation. In the present work we present the positive effects of physical activity in elderly and a study where the effects of a 8-week period of functional electrical stimulation and strength training with proprioceptive stimulation in elderly are compared.

Age-Related Changes in Morphology and Function of Scapular Muscles in Asymptomatic People

PM&R ◽  
2017 ◽  
Vol 9 (9) ◽  
pp. 892-900 ◽  
Author(s):  
Shuhei Morise ◽  
Takayuki Muraki ◽  
Hiroaki Ishikawa ◽  
Shin-Ichi Izumi
Keyword(s):  
Age Related ◽  
And Function ◽  
Age Related Changes

scholarly journals Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia: A Mini-Review

Gerontology ◽  
2017 ◽  
Vol 63 (6) ◽  
pp. 580-589 ◽  
Author(s):  
Juan Diego Naranjo ◽  
Jenna L. Dziki ◽  
Stephen F. Badylak
Keyword(s):  
Regenerative Medicine ◽  
Treatment Options ◽  
The Elderly ◽  
Signaling Molecules ◽  
Current Treatment ◽  
Muscle Physiology ◽  
Age Related ◽  
Increased Risk ◽  
And Function ◽  
Age Related Changes

Sarcopenia is a complex and multifactorial disease that includes a decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls. Treatment options are suboptimal and consist of exercise and nutrition as the cornerstone of therapy. Current treatment principles involve identification and modification of risk factors to prevent the disease, but these efforts are of limited value to the elderly individuals currently affected by sarcopenia. The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. The present paper reviews regenerative medicine strategies that seek to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach that is discussed herein.

Neuroimaging Approaches for Elderly Studies

2017 ◽  
pp. 1576-1617
Author(s):  
Charis Styliadis ◽  
Panagiotis Kartsidis ◽  
Evangelos Paraskevopoulos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structure And Function ◽  
Cognitive Capacity ◽  
Aging Brain ◽  
Cerebral Structure ◽  
Age Related ◽  
Elderly Populations ◽  
And Function ◽  
Age Related Changes

Advances in the field of neuroimaging have allowed for the examination of the effects of age-related changes on cognitive capacity in elderly populations. Structural techniques are now routinely used to report cortical atrophic rates in aging and particularly within the context of the Alzheimer's disease, and may be integrated with functional techniques which examine the functional characteristics of the cortex at rest and during the performance of a task. Despite advancing age cognitive function remains highly plastic, allowing for interventions that aim to maintain or even remediate its capacity and the mechanisms by which structure and function are altered among seniors. Overall, information on the integrity of the cerebral structure and function aid in the early detection and treatment of the Alzheimer's disease as well as the evaluation and track of the disease's progression. In this chapter, neuroimaging methods are presented along with findings that are particularly relevant for the study of neuroplasticity in the aging brain.

Managing expectations: How stress, social support, and aging attitudes affect awareness of age-related changes

2019 ◽  
Vol 37 (3) ◽  
pp. 986-1007
Author(s):  
Erica L. O’Brien ◽  
Neika Sharifian
Keyword(s):  
Social Support ◽  
Online Survey ◽  
Well Being ◽  
Age Related ◽  
Aging Attitudes ◽  
Amazon's Mechanical Turk ◽  
And Function ◽  
Gains And Losses ◽  
Future Work ◽  
Age Related Changes

The degree to which social support (SS) moderates the effects of stress on self-perceptions of aging may depend on individual differences in general aging attitudes. We examined how stress, different types of SS, and general expectations regarding aging (ERA) affect awareness of age-related changes (AARCs). The sample included 137 adults (21–76 years; 56.2% women) who took an online survey on Amazon’s Mechanical Turk. Regression analyses showed differential moderation of stress effects due to ERA and the SS measure (perceived and received) and function (emotional and instrumental). Received emotional SS was only associated with AARC losses, whereas perceived support—both emotional and instrumental—was associated with AARC gains and losses. Findings may help guide future work aimed at promoting health and well-being in adulthood.

Sign in / Sign up

Export Citation Format

Share Document