Biology subjects

Takakura, Y.

Publications and source records attributed to Takakura, Y..

4 recordsLinked to original sources

bioRxiv2026

A chromatin relay from AIRE to ETS transcription factors sustains peripheral antigen expression in the thymic mimetic cells to ensure central tolerance.

Medullary thymic epithelial cells (mTECs) establish central tolerance by expressing a diverse repertoire of peripheral tissue-specific antigens (TSAs). This diversity is regulated not only by the transcriptional regulator AIRE, but also by lineage-defining factors in tissue-mimetic, AIRE-negative descendants of Aire mTECs (post-Aire mimetic TECs). However, whether and how prior AIRE activity contributes to TSA expression in post-AIRE mimetic TECs remains unclear. Here, we identify the ETS transcription factors, EHF and ELF3, as key regulators that sustain AIRE-primed gene expression in these cells. EHF and ELF3 preferentially bind distal genomic regions which are rendered accessible in advance by AIRE. Combined loss of EHF and ELF3 disrupts expression of AIRE-regulated genes expressed in mimetic TECs, leading to tissue-selective autoimmunity. Our findings reveal a relay mechanism in which AIRE primes chromatin for ETS factors to maintain TSA expression in post-AIRE mimetic TECs, thereby safeguarding self-tolerance.

immunology↗

bioRxiv2023

Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unknown mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48 induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 showed a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice developed autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

cell biology↗

bioRxiv2023

Correlation of blood TCR repertoire with an organ manifestation in a mouse model of autoimmune disease

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCR and {beta} repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCR and {beta} of CD4+CD44highCD62Llow T cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.

immunology↗

bioRxiv2021

Integrative analysis of scRNAs-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regulator

Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by transcriptional regulator AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected by using Fucci technology express a minimal level of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit amplifying Aire+mTEC precursors during Aire+mTEC differentiation process of the postnatal thymus.

immunology↗