Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection DOI Creative Commons

Andrei Belean,

Eden Xue,

Benjamin Cisneros

et al.

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

Published: June 4, 2024

Introduction Herpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections made it difficult establish a causal relationship between acute infection subsequent development autoimmunity. We shown that murine roseolovirus (MRV), which is highly related human induces thymic atrophy disruption central tolerance after neonatal infection. Moreover, MRV results in autoimmunity adult mice, long resolution This suggests durable immune dysregulation. Methods In current studies, we utilized single-cell RNA sequencing (scRNAseq) study tropism thymus determine cellular processes were disrupted by then data cell culture system. Results Herein, describe how alters transcriptome during found resulted major shifts inflammatory, differentiation cycle pathways infected thymus. also observed relative number specific populations. utilizing expression late viral transcripts as proxy replication, identified approach demonstrated double negative, positive, CD4 single positive thymocytes, well medullary epithelial cells vivo . Finally, applying pseudotime analysis transcripts, refer “pseudokinetics,” gene transcription patterns associated with types status. this information first systems susceptible vitro Conclusion Our research provides complete picture Additionally, transcriptomic alterations populations These studies offer important insight into early events occur disrupt promote

Language: Английский

Sterile production of interferons in the thymus affects T cell repertoire selection DOI
K. Maude Ashby, Matouš Vobořil, Oscar Camilo Salgado

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(97)

Published: July 26, 2024

Type I and III interferons (IFNs) are robustly induced during infections protect cells against viral infection. Both type IFNs also produced at low levels in the thymus steady state; however, their role T cell development immune tolerance is unclear. Here, we found that both were constitutively by a very small number of AIRE + murine thymic epithelial cells, independent microbial stimulation. Antigen-presenting highly responsive to IFNs, required for activation maturation 1 conventional dendritic macrophages, B cells. Loss IFN sensing led reduced regulatory selection, receptor (TCR) repertoire diversity, enhanced autoreactive responses self-antigens expressed peripheral signaling. Thus, constitutive exposure generating tolerant diverse TCR repertoire.

Language: Английский

Citations

10
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
Thymus ad astra, or spaceflight-induced thymic involution DOI Creative Commons
Wataru Muramatsu, Maria Maryanovich, Taishin Akiyama

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 24, 2025

Spaceflight imposes a constellation of physiological challenges—cosmic radiation, microgravity, disrupted circadian rhythms, and psychosocial stress—that critically compromise astronaut health. Among the most vulnerable organs is thymus, cornerstone immune system functionality, tasked with generating naive T cells essential for adaptive immunity. The thymus particularly sensitive to spaceflight conditions, as its role in maintaining homeostasis tightly regulated by balance systemic local factors easily space. Cosmic an omnipresent hazard beyond Earth’s magnetosphere, accelerates DNA damage cellular senescence thymic epithelial cells, impairing thymopoiesis increasing risk dysregulation. Microgravity rhythm disruption exacerbate this altering cell migration patterns stromal support, critical T-cell development. Psychosocial stressors, including prolonged isolation mission-induced anxiety, further compound atrophy elevating glucocorticoid levels. Ground-based analogs simulating cosmic radiation microgravity have been instrumental elucidating mechanisms involution downstream effects on These models reveal that long-duration missions result diminished output, leaving astronauts infections possibly at high developing neoplasia. Advances countermeasures, such pharmacological interventions targeting regeneration bioengineering approaches protect architecture, are emerging vital strategies preserve resilience during space exploration. Focusing central hub vulnerability underscores pivotal spaceflight-induced health risks. Understanding these dynamics will not only enhance safety human but also provide insights into biology under extreme conditions.

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
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
Interferon autoantibodies as signals of a sick thymus DOI Creative Commons
Bergithe E Oftedal,

Thea Sjøgren,

Anette S. B. Wolff

et al.

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

Published: Feb. 22, 2024

Type I interferons (IFN-I) are key immune messenger molecules that play an important role in viral defense. They act as a bridge between microbe sensing, function magnitude, and adaptive immunity to fight infections, they must therefore be tightly regulated. It has become increasingly evident thymic irregularities mutations genes affecting tolerance can lead the production of IFN-I autoantibodies (autoAbs). Whether these biomarkers affect system or tissue integrity host is still controversial, but new data show autoAbs may increase susceptibility severe disease caused by certain viruses, including SARS-CoV-2, herpes zoster, varicella pneumonia. In this article, we will elaborate on disorders have been identified with autoAbs, discuss models how IFN-Is lost, explain consequences for host.

Language: Английский

Citations

3
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

3
Systemic inflammatory Th1 cytokines during Trypanosoma cruzi infection disrupt the typical anatomical cell distribution and phenotypic/functional characteristics of various cell subsets within the thymus DOI
María Estefanía Viano, Natalia Soledad Baez, Constanza Savid-Frontera

et al.

Microbes and Infection, Journal Year: 2024, Volume and Issue: 26(5-6), P. 105337 - 105337

Published: April 13, 2024

Language: Английский

Citations

1
Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection DOI Creative Commons

Andrei Belean,

Eden Xue,

Benjamin Cisneros

et al.

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

Published: June 4, 2024

Introduction Herpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections made it difficult establish a causal relationship between acute infection subsequent development autoimmunity. We shown that murine roseolovirus (MRV), which is highly related human induces thymic atrophy disruption central tolerance after neonatal infection. Moreover, MRV results in autoimmunity adult mice, long resolution This suggests durable immune dysregulation. Methods In current studies, we utilized single-cell RNA sequencing (scRNAseq) study tropism thymus determine cellular processes were disrupted by then data cell culture system. Results Herein, describe how alters transcriptome during found resulted major shifts inflammatory, differentiation cycle pathways infected thymus. also observed relative number specific populations. utilizing expression late viral transcripts as proxy replication, identified approach demonstrated double negative, positive, CD4 single positive thymocytes, well medullary epithelial cells vivo . Finally, applying pseudotime analysis transcripts, refer “pseudokinetics,” gene transcription patterns associated with types status. this information first systems susceptible vitro Conclusion Our research provides complete picture Additionally, transcriptomic alterations populations These studies offer important insight into early events occur disrupt promote

Language: Английский

Citations

0