Direct and indirect RANK and CD40 signaling regulate the maintenance of thymic epithelial cell frequency and properties in the adult thymus DOI Creative Commons

Mio Hayama,

Hiroto Ishii,

Maki Miyauchi

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 29, 2024

Medullary thymic epithelial cells (mTECs) play a crucial role in suppressing the onset of autoimmunity by eliminating autoreactive T and promoting development regulatory thymus. Although mTECs undergo turnover adults, molecular mechanisms behind this process remain unclear. This study describes direct indirect roles receptor activator NF-κB (RANK) CD40 signaling TECs adult Flow cytometric single-cell RNA-seq (scRNA-seq) analyses suggest that depletion both RANK inhibits mTEC differentiation from CCL21

Language: Английский

Establishment of a microwell-array-based miniaturized thymic organoid model suitable for high-throughput applications DOI Creative Commons

Viktoria Major,

Sam Palmer, Paul Rouse

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115579 - 115579

Published: April 16, 2025

Language: Английский

Citations

1
The thymus road to a T cell: migration, selection, and atrophy DOI Creative Commons
Mario Pérez, Peter Vandenabeele, Peter Tougaard

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 27, 2024

The thymus plays a pivotal role in generating highly-diverse repertoire of T lymphocytes while preventing autoimmunity. Thymus seeding progenitors (TSPs) are heterogeneous group multipotent that migrate to the via CCR7 and CCR9 receptors. While NOTCH guides toward cell fate, absence or disruption signaling renders microenvironment permissive other fates. Following commitment, developing cells undergo multiple selection checkpoints by engaging with extracellular matrix, interacting thymic epithelial (TECs) immune subsets across different compartments thymus. assess receptor (TCR) performance, failure resulting either repurposing (agonist selection), death. Additionally, environmental cues such as inflammation endocrine induce acute atrophy, contributing demise most during selection. We discuss occurrence atrophy response systemic inflammation. demonstrates high plasticity, shaping abrogating development undergoing profound structural changes, facilitating regeneration restoration once is resolved. Despite challenges, ensures highly diverse capable discerning between self non-self antigens, ultimately egressing secondary lymphoid organs where they complete their maturation exert functions.

Language: Английский

Citations

7
Coordinated changes in thymic stromal and hematopoietic cells that define the perinatal to juvenile transition DOI Open Access
Anusha Vasudev, Colin E. Moore,

Aparna Calindi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

SUMMARY T cells in the perinatal thymus have distinct phenotypes and functions that may be instructed by age-specific features of microenvironment. We evaluated molecular cellular profiles thymic stromal cells, including epithelial (TECs), mesenchyme, endothelium, hematopoietic antigen presenting (hAPCs), from birth through one-month age mice. Single-cell transcriptional profiling, flow cytometry, immunohistochemistry revealed coordinated changes accompanied altered thymocyte differentiation at defined transitional ages during shift growth to juvenile homeostasis, which was mirrored humans. These analyses link diminished IGF2 expression mesenchymal with activation RB pathway TECs transition. Moreover, a increase type I interferon signaling stroma across transition is associated processing presentation signatures hAPCs. Collectively, these datasets provide resource interrogate

Language: Английский

Citations

0
Sterile production of interferons in the thymus DOI
Ryan J. Martinez, Kristin A. Hogquist

The Journal of Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract T-cell central tolerance is controlled by thymocyte TCR recognition of self-peptides presented thymic APCs. While epithelial cells are essential for tolerance, a variety other traditional APCs also play critical roles in selection. Similar to how peripheral require activation become effective, tolerogenic. Recent studies have identified IFNs as an factor the and generation optimally tolerogenic environment. In this review, we focus on interferon (IFN) production within thymus its effects developing thymocytes. We examine importance IFN itself well interferon-stimulated proteins generated during immune responses.

Language: Английский

Citations

0
Type I and type III interferon receptor knockout chickens: Novel models for unraveling interferon dynamics in influenza infection DOI Creative Commons
Mohanned Naif Alhussien, Hanna Vikkula,

Romina Klinger

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract The rapid cross-species transmission of highly pathogenic avian influenza presents a significant zoonotic threat. Elucidating the interferon (IFN) system, primary antiviral defense in chickens, is critical for controlling virus at its source and preventing spillover into humans other species. We engineered type I (IFN-α/β) III (IFN-λ) IFN receptor knockout chickens to dissect role IFNs viral infections. Results revealed that predominantly modulates innate immune cell populations, T subsets, their contribution antibody production following immunization under physiological conditions. In ovo vivo challenge experiments utilizing diverse A strains demonstrated strain-specific roles both IFN-α/β IFN-λ orchestrating pathogenesis, immunological responses, tissue-tropism effects. Notably, was particularly crucial initial mechanisms against H3N1 infection. These novel models offer unprecedented insights biology within context influenza, which essential developing more effective strategies prevent control this public health challenge.

Language: Английский

Citations

0
Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα DOI Creative Commons

Artur Stoljar,

Maksym Zarodniuk,

Rudolf Bichele

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(7)

Published: March 28, 2025

Recent studies have highlighted the role of thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies interferon-alpha (IFNα). Unlike mice, Aire-deficient rats robust IFNα. Using this rat model, we show that Aire regulates expression interferon-stimulated genes (ISGs), which occurs before developing anti-IFNα autoantibodies. In periphery, observed a widespread downregulation ISGs across cells and reduced activation natural killer (NK) cells. Furthermore, presence correlated peripheral tissue inflammation, suggesting their dampening T1 IFN signaling minimizing infiltration. Our findings reveal Aire-mediated regulation is linked production protective autoantibodies, inversely correlate pathology tissues.

Language: Английский

Citations

0
Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development DOI
Abdulvasey Mohammed,

Wenqing Wang,

Martin Arreola

et al.

Science Immunology, Journal Year: 2025, Volume and Issue: 10(107)

Published: May 2, 2025

Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving differentiation remain incompletely understood. Here, we elucidated pathways instructing human cell development the context other anterior foregut–derived organs. Activation interferon response gene regulatory networks distinguished cells thymus from those Thymic cortex medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored effects type I II interferons on progenitor induced pluripotent stem cells. Type was essential for expressing proteasome antigen-presenting molecules, whereas or were inducing different cytokines Our findings suggest that are critical to cortical medullary differentiation.

Language: Английский

Citations

0
Antigen presentation for central tolerance induction DOI
Ludger Klein, Elisabetta Petrozziello

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

Citations

2
Direct and indirect RANK ligand and CD40 ligand signaling regulate the maintenance of thymic epithelial cell frequency and properties in the adult thymus DOI Creative Commons

Mio Hayama,

Hiroto Ishii,

Maki Miyauchi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 13, 2024

Abstract Medullary thymic epithelial cells (mTECs) play a crucial role in suppressing the onset of autoimmunity by eliminating autoreactive T and promoting development regulatory thymus. Although mTECs undergo turnover adults, molecular mechanisms behind this process remain unclear. This study describes direct indirect roles receptor activator NF-κB ligand (RANKL) CD40 (CD40L) signaling TECs adult Flow cytometric single-cell RNA-seq (scRNA-seq) analyses suggest that depletion both RANKL CD40L inhibits mTEC differentiation from CCL21 + progenitors to transit-amplifying Unexpectedly, also indirectly affects gene expression TEC cortical TECs. Notably, AP-1 expression, which allows further subdivision progenitors, is upregulated following signaling. Overall, our data propose cooperatively maintain mature frequency thymus sustain characteristics through an mechanism.

Language: Английский

Citations

0
Direct and indirect RANK and CD40 signaling regulate the maintenance of thymic epithelial cell frequency and properties in the adult thymus DOI Creative Commons

Mio Hayama,

Hiroto Ishii,

Maki Miyauchi

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 29, 2024

Medullary thymic epithelial cells (mTECs) play a crucial role in suppressing the onset of autoimmunity by eliminating autoreactive T and promoting development regulatory thymus. Although mTECs undergo turnover adults, molecular mechanisms behind this process remain unclear. This study describes direct indirect roles receptor activator NF-κB (RANK) CD40 signaling TECs adult Flow cytometric single-cell RNA-seq (scRNA-seq) analyses suggest that depletion both RANK inhibits mTEC differentiation from CCL21

Language: Английский

Citations

0