Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of Self-Antigens

The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs n...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2022-01, Vol.208 (2), p.303-320
Main Authors: Nishijima, Hitoshi, Matsumoto, Minoru, Morimoto, Junko, Hosomichi, Kazuyoshi, Akiyama, Nobuko, Akiyama, Taishin, Oya, Takeshi, Tsuneyama, Koichi, Yoshida, Hideyuki, Matsumoto, Mitsuru
Format: Article
Language:English
Subjects:
AIRE Protein
Animals
Autoantigens - immunology
Autoimmunity - genetics
Autoimmunity - immunology
Chemokines, CC - genetics
Chemokines, CC - metabolism
Epithelial Cells - immunology
Gene Expression Regulation
Gene Knock-In Techniques
Gene Knockout Techniques
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Thymus Gland - cytology
Thymus Gland - immunology
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic - genetics
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Summary:The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire's primary targets while distinguishing them from the secondary targets.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2100692