The thymus plays an important role in the development of self-tolerance 32and regulatory T cells; hence, dysfunction of the thymus is a cause of im-munodeficiency and autoimmune diseases. The objectives of this study are: 1) to identify the molecular and cellular mechanisms that regulate T cell selection and differentiation in the thymus, 2) to elucidate the mechanisms underlying the development of immune-related diseases caused by thymic dysfunction, and 3) to clarify the effects of environmental changes, including aging, on thy-mic function and its underlying mechanisms.Autophagy is a process in which cytoplasmic components of a cell are trans-ported to lysosomes and degraded by multiple enzymes. Initiation of autophagy typically depends on “cellular stress”, such as starvation or mitochondrial dam-age. However, in thymic epithelial cells (TECs), autophagy is constitutively activated in a stress-independent manner. The stress-independent autophagy is reportedly critical for self-antigen presentation by TECs through the degra-dation of self-proteins in the cytosol. Despite its importance, the mechanisms inducing stress-independent autophagy in TECs remain largely unknown. We found that the mitochondrial protein C15ORF48 is a critical inducer of stress-independent autophagy in TECs. Single-cell RNA-seq analysis suggested high expression of C15orf48 genes in mature types of TECs. C15orf48-deficient mice show reduced stress-independent autophagy in the TEC, but not in the typical starvation-induced autophagy in skeletal muscle. This suggests that C15ORF48 is not a general autophagy-related factor but plays a specific role in stress-in-dependent autophagy. Furthermore, depletion of C15ORF48 in thymic stroma cells caused spontaneous autoimmunity, suggesting that C15ORF48-induced autophagy in TECs is important for TEC-dependent self-tolerance. Mechanisti-cally, C15ORF48 is induced by NF-κB activation signaling and is localized in mitochondria. C15ORF48 decreases mitochondrial membrane potential and intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Overall, these results suggest that mi-tochondrial C15ORF48 controls stress-independent autophagy in TECs and thereby regulates central self-tolerance.Figure: C15ORF48 is critical for stress-indepen-dent autophagy in thymic epithelial cellsThymus sections from wild-type and C15orf48-/- mice were stained with anti-GFP (LC3; an autophagosome marker), anti-Keratin 5 antibodies (a marker for medul-lary TECs) and DAPI (nucleus). GFP-LC3 puncta in the Keratin 5-positive area are indicated by arrows.Recent Major PublicationsHorie K, Namiki K, Kinoshita K, Miyauchi M, Ishikawa T, Hayama M, Maruyama Y, Hagiwara N, Miyao T, Murata S, Kobayashi TJ, Akiyama N, Akiyama T. Acute irradiation causes a long-term disturbance in the heterogeneity and gene expression profile of medullary thymic epithe-lial cells. Front Immunol 14, 1186154 (2023)Katayama Y, Yokota R, Akiyama T, Kobayashi TJ. Machine Learning Approaches to TCR Repertoire Analysis. Front Immunol 13, 858057 (2022)Miyao T, Miyauchi M, Kelly ST, Terooatea TW, Ishikawa T, Oh E, Hirai S, Horie K, Takakura Y, Ohki H, Hayama M, Maruyama Y, Seki T, Ishii H, Yabukami H, Yoshida M, Inoue A, Sakaue-Sawano A, Miyawaki A, Muratani M, Minoda A, Akiyam N, Akiyama T. Integrative analysis of scRNA-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regula-tor. Elife 11, e73998 (2022)Invited presentationsAkiyama T. “Crosstalk and differentiation variation of thymic epithelial cells and T cells by single-cell multi-layer analysis” Kick-off meeting for Joint Research Cen-ter for Medical Biology of Virus and Stem Cell Systems (Kyoto, Japan)Laboratory for Immune HomeostasisTeam Leader: Taishin Akiyama
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