scholarly journals RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla

2007 ◽  
Vol 204 (6) ◽  
pp. 1267-1272 ◽  
Author(s):  
Simona W. Rossi ◽  
Mi-Yeon Kim ◽  
Andreas Leibbrandt ◽  
Sonia M. Parnell ◽  
William E. Jenkinson ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Thymic Epithelial Cells ◽  
Receptor Repertoire ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells ◽  
Functional Regulation ◽  
Lymphoid Structures

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.

scholarly journals T Cell Receptor (TCR)-induced Death of Immature CD4+CD8+ Thymocytes by Two Distinct Mechanisms Differing in Their Requirement for CD28 Costimulation: Implications for Negative Selection in the Thymus

1997 ◽  
Vol 186 (11) ◽  
pp. 1911-1922 ◽  
Author(s):  
Jennifer A. Punt ◽  
Wendy Havran ◽  
Ryo Abe ◽  
Apurva Sarin ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Clonal Deletion ◽  
Receptor Repertoire ◽  
Cd28 Costimulation ◽  
Thymic Medulla ◽  
Costimulatory Signals ◽  
Tcr Signals

Negative selection is the process by which the developing lymphocyte receptor repertoire rids itself of autoreactive specificities. One mechanism of negative selection in developing T cells is the induction of apoptosis in immature CD4+CD8+ (DP) thymocytes, referred to as clonal deletion. Clonal deletion is necessarily T cell receptor (TCR) specific, but TCR signals alone are not lethal to purified DP thymocytes. Here, we identify two distinct mechanisms by which TCR-specific death of DP thymocytes can be induced. One mechanism requires simultaneous TCR and costimulatory signals initiated by CD28. The other mechanism is initiated by TCR signals in the absence of simultaneous costimulatory signals and is mediated by subsequent interaction with antigen-presenting cells. We propose that these mechanisms represent two distinct clonal deletion strategies that are differentially implemented during development depending on whether immature thymocytes encounter antigen in the thymic cortex or thymic medulla.

scholarly journals The Ubiquitin-like Modifier FAT10 Is Selectively Expressed in Medullary Thymic Epithelial Cells and Modifies T Cell Selection

2015 ◽  
Vol 195 (9) ◽  
pp. 4106-4116 ◽  
Author(s):  
Stefanie Buerger ◽  
Valerie L. Herrmann ◽  
Sarah Mundt ◽  
Nico Trautwein ◽  
Marcus Groettrup ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Cell Selection ◽  
Medullary Thymic Epithelial Cells ◽  
T Cell Selection

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

2010 ◽  
Vol 11 (6) ◽  
pp. 512-519 ◽  
Author(s):  
Maria Hinterberger ◽  
Martin Aichinger ◽  
Olivia Prazeres da Costa ◽  
David Voehringer ◽  
Reinhard Hoffmann ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Medullary Thymic Epithelial Cells

scholarly journals Ageing compromises mouse thymus function and remodels epithelial cell differentiation

2020 ◽  
Author(s):  
J Baran-Gale ◽  
MD Morgan ◽  
S Maio ◽  
F Dhalla ◽  
I Calvo-Asensio ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Lymphoid Organ ◽  
Precursor Cell ◽  
Lineage Tracing ◽  
Thymic Epithelial Cells ◽  
Cellular Mechanisms ◽  
Receptor Repertoire ◽  
Mouse Cortex ◽  
Repertoire Diversity

AbstractAgeing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the function of mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.

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 CCL25 increases thymopoiesis after androgen withdrawal

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3255-3263 ◽  
Author(s):  
Kirsten M. Williams ◽  
Philip J. Lucas ◽  
Catherine V. Bare ◽  
Jiun Wang ◽  
Yu-Waye Chu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Thymic Epithelial Cells ◽  
Thymocyte Development ◽  
Immature Thymocyte ◽  
Early Increase ◽  
Androgen Withdrawal

Abstract Although studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA+ thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA+ TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal.

scholarly journals The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development

2013 ◽  
Vol 210 (4) ◽  
pp. 675-681 ◽  
Author(s):  
Jennifer E. Cowan ◽  
Sonia M. Parnell ◽  
Kyoko Nakamura ◽  
Jorge H. Caamano ◽  
Peter J.L. Lane ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Cell Development ◽  
Thymic Epithelial Cells ◽  
Thymocyte Development ◽  
Single Positive ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells

A key role of the thymic medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.

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