Revisiting Aire and tissue-restricted antigens at single-cell resolution

Abstract

The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the “education” of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.

The ribonucleoprotein-mediated CRISPR–Cas9 system induces recurrent Aire gene mutations in contrast to the nickase expression vector in murinein vitroorin vivomodels

“…We investigated the mutational consequences of using an identical CRISPR-Cas9 system of in vitro cultured murine medullary thymic epithelial cells (mTECs) and in vivo blastocysts to generate edited mice. We targeted the autoimmune regulator (Aire) gene because it is the primary transcriptional regulator in mTECs controlling the expression of a large set of peripheral tissue antigen (PTA) genes, which are essential during the negative selection of autoreactive thymocytes in the thymus that prevents aggressive autoimmunity in the periphery (2, 27, 28).…”

Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis

“…The late mTEC stages comprise of post-Aire cornified (Krt10 + ) mTECs ( 84 , 85 ) as well as Tuft-mTECs (Dclk1 + ) ( 72 , 77 , 86 , 87 ), microfold mTECs (Gp2 + ), enterocyte/hepatocyte mTECs (Hnf4 + ), keratinocyte-like mTECs (Grhl + ), neuroendocrine mTECs (Foxa+), cilitated mTECs (Foxj1 + ) and other mimetic mTECs ( 88 , 89 ). Previous reports on thymic cell populations that represent characteristics of peripheral differentiated cell types and expression of mimetic cell genes in the thymus were initially difficult to distinguish from features of promiscuous gene expression of peripheral antigens, however single-cell technologies and high throughput assays enabled a revised view on those findings, leading to the identification of several distinct mimetic cell populations in the thymus with characteristic gene expression profiles, lineage-specific transcription factors, phenotypical characteristics and probably specific functions in the thymus reviewed in other review articles in more detail ( 90 , 91 ). The mature mTEC population is subject to high turnover with a half-life of 12-14 days ( 92 , 93 ), thus leading to a constant change in self-antigen co-expression groups over the course of mTEC development and lifetime.…”

“…The mode of action of the transcriptional regulator Aire is at the epigenetic level, by acting on transcriptional elongation and by acting on superenhancers ( 107 , 108 ). Aire is interacting with a multitude of different factors identified so far, including proteins involved in nuclear transport (HDAC1, HDAC2) ( 109 ), chromatin-modifiers (H3K4me0) ( 110 , 111 ), transcriptional regulators (RNA PolII, DNA-PK, P-TEFb, HNRNPL, BRD4) ( 102 , 112 – 116 ), and proteins involved in mRNA processing (JMJD6) ( 117 ) which is reviewed in other articles in more detail ( 91 , 101 , 118 ). The mode of action of the transcription factor Fezf2 on the other hand, is through consensus binding site recognition.…”

Expression Level of Autoimmune Regulator In B Cells Correlates With Residual Islet β Cell Function In Type 1 Diabetes Mellitus

“…The autoimmune regulator (Aire) is a transcriptional factor regulating the expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) [1][2][3][4][5][6]. TRAs induced by Aire are presented on the surface of the cells and tightly interacted with the thymocytes with auto-reactivity to delete them, a procedure referred as negative selection, meaning [7] only thymocytes without auto-reactivity could survive during their development. Through this mechanism, Aire maintains central immune tolerance [2,3,5].…”