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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Cexun Hu ◽  
Keyu Zhang ◽  
Feng Jiang ◽  
Hui Wang ◽  
Qixiang Shao
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Epigenetic Modification ◽  
Emerging Infectious Diseases ◽  
Epigenetic Modifications ◽  
Thymic Epithelial Cells ◽  
Main Body ◽  
Human Beings ◽  
Age Related ◽  
Thymus Atrophy

Abstract 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.

scholarly journals In Pursuit of Adult Progenitors of Thymic Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Tatsuya Ishikawa ◽  
Nobuko Akiyama ◽  
Taishin Akiyama
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Adaptive Immune System ◽  
Thymic Epithelial Cells ◽  
Adaptive Immune ◽  
Peripheral T Cells ◽  
Robust Adaptive ◽  
Adult Thymus ◽  
Shed Light ◽  
Selection Of

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.

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 Cathepsin L Regulates CD4+ T Cell Selection Independently of Its Effect on Invariant Chain

2002 ◽  
Vol 195 (10) ◽  
pp. 1349-1358 ◽  
Author(s):  
Karen Honey ◽  
Terry Nakagawa ◽  
Christoph Peters ◽  
Alexander Rudensky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Positive Selection ◽  
Cathepsin L ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
Invariant Chain ◽  
Cell Selection ◽  
T Cell Selection

CD4+ T cells are positively selected in the thymus on peptides presented in the context of major histocompatibility complex class II molecules expressed on cortical thymic epithelial cells. Molecules regulating this peptide presentation play a role in determining the outcome of positive selection. Cathepsin L mediates invariant chain processing in cortical thymic epithelial cells, and animals of the I-Ab haplotype deficient in this enzyme exhibit impaired CD4+ T cell selection. To determine whether the selection defect is due solely to the block in invariant chain cleavage we analyzed cathepsin L–deficient mice expressing the I-Aq haplotype which has little dependence upon invariant chain processing for peptide presentation. Our data indicate the cathepsin L defect in CD4+ T cell selection is haplotype independent, and thus imply it is independent of invariant chain degradation. This was confirmed by analysis of I-Ab mice deficient in both cathepsin L and invariant chain. We show that the defect in positive selection in the cathepsin L−/− thymus is specific for CD4+ T cells that can be selected in a wild-type and provide evidence that the repertoire of T cells selected differs from that in wild-type mice, suggesting cortical thymic epithelial cells in cathepsin L knockout mice express an altered peptide repertoire. Thus, we propose a novel role for cathepsin L in regulating positive selection by generating the major histocompatibility complex class II bound peptide ligands presented by cortical thymic epithelial cells.

scholarly journals TGF-β signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 626-634 ◽  
Author(s):  
Mathias M. Hauri-Hohl ◽  
Saulius Zuklys ◽  
Marcel P. Keller ◽  
Lukas T. Jeker ◽  
Thomas Barthlott ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Epithelial Cells ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Stromal Compartment ◽  
Hematopoietic Stem

Abstract The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-β signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-βRII on thymic epithelial cells. Moreover, TGF-β signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-β signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation.

RB Controls Size, Cellularity, and T Cell Output of the Mouse Thymus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 835-835
Author(s):  
Phillip M. Garfin ◽  
Patrick Viatour ◽  
Dullei Min ◽  
Jerrod Bryson ◽  
Kenneth I. Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Conflicts Of Interest ◽  
Thymic Epithelial Cells ◽  
Main Function ◽  
Thymic Involution ◽  
Regulatory Relationship ◽  
Thymic Tissue ◽  
Rb Pathway

Abstract Abstract 835 The establishment of the thymic microenvironment early in life is crucial for the production functional T cells. Conversely, thymic involution results in a decreased T cell output. Thymic involution has important health implications especially following bone marrow transplant. Our objective is to determine molecular and cellular mechanisms that will allow for regeneration of involuted thymic tissue, restore production of naïve T cells, and improve immune function while improving our understanding of immunobiology. In this pursuit, we have focused on the Retinoblastoma family of tumor suppressor proteins. The main function of the RB pathway is to restrict passage through the G1/S transition of the cell cycle. RB and its two family members, p107 and p130, mediate the action of a broad range of cellular signals to control the proliferation, survival, and differentiation status of a large number of mammalian cell types. We found that inactivation of the RB pathway in the thymus by early deletion of RB family genes prevents thymic involution, promotes expansion of functional thymic epithelial cells (TECs), and increases thymic T cell output. Moreover, we have identified a direct regulatory relationship between RB and the Foxn1 transcription factor Via E2F transcription factors, where RB/E2F complexes directly repress the Foxn1 promoter, thereby promoting involution. Thus, the RB family is a critical mediator of extra- and intra-cellular signals to regulate thymic epithelial cells and thymus function, and decreasing RB pathway function may promote regeneration of the involuted thymus and restoration of naïve T cell production in patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy.

1990 ◽  
Vol 171 (4) ◽  
pp. 1101-1121 ◽  
Author(s):  
E K Gao ◽  
D Lo ◽  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Tolerance Induction ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Cd4 Cells ◽  
Clonal Deletion ◽  
Host Type

T cell tolerance induction was examined in long-term H-2-heterozygous parent----F1 chimeras prepared with supralethal irradiation (1,300 rad). Although these chimeras appeared to be devoid of host-type APC, the donor T cells developing in the chimeras showed marked tolerance to host-type H-2 determinants. Tolerance to the host appeared to be virtually complete in four assay systems: (a) primary mixed lymphocyte reactions (MLR) of purified lymph node (LN) CD8+ cells (+/- IL-2); (b) primary MLR of CD4+ (CD8-) thymocytes; (c) skin graft rejection; and (d) induction of lethal graft-vs.-host disease by CD4+ cells. Similar tolerance was observed in chimeras given double irradiation. The only assay in which the chimera T cells failed to show near-total tolerance to the host was the primary MLR of post-thymic CD4+ cells. In this assay, LN CD4+ cells regularly gave a significant antihost MLR. The magnitude of this response was two- to fourfold less than the response of normal parental strain CD4+ cells and, in I-E(-)----I-E+ chimeras, was paralleled by approximately 70% deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the chimeras presumably occurred in the thymus itself. The failure to detect host APC in the thymus implies that tolerance reflected contact with thymic epithelial cells (and/or other non-BM-derived cells in the thymus). To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells but spared a proportion of these cells (possibly low affinity cells). Since these latter cells appeared to be functionally inert in the thymus (in contrast to LN), we suggest that the thymic epithelial cells induced a temporary form of anergy in the remaining host-reactive thymocytes. This anergic state disappeared when the T cells left the thymus and reached LN.

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