Transposable Elements Extensively Regulate Thymus Development and Function

Core Concepts

Transposable elements (TEs) are highly expressed in the thymus, particularly in medullary thymic epithelial cells (mTECs) and plasmacytoid dendritic cells (pDCs), where they interact with transcription factors essential for thymic development and function, generate MHC-I-associated peptides, and trigger innate immune responses.

Abstract

The study investigated the role of transposable elements (TEs) in T cell development and thymus function using multi-omic analyses of human and mouse thymic cells.
Key highlights:

TE expression in the human thymus shows extensive age- and cell lineage-related variations, with LINE and SINE subfamilies exhibiting high and shared expression across cell types, while LTR subfamilies show more cell-type specific patterns.
TEs form complex interactions with transcription factors (TFs) crucial for thymic development and function, particularly in mTECs, where TEs may provide binding sites for TFs like PAX1 and NF-κB.
Two thymic cell types stand out for their broad and distinct TE expression profiles: pDCs express a highly diverse repertoire of LTRs, SINEs, and LINEs, while mTEC(II) show heterogeneous overexpression of LTR subfamilies.
The high TE expression in thymic pDCs is associated with the formation of double-stranded RNAs, potentially explaining their constitutive secretion of type I interferons.
In mouse mTECs, the transcription factors AIRE, FEZF2, and CHD4 regulate non-redundant sets of TE sequences, some of which are presented as MHC-I-associated peptides.
These findings highlight the diverse interactions between TEs and the adaptive immune system in the thymus, suggesting that orchestrating TE expression is critical to prevent autoimmunity.

Stats

Transposable elements represent ~45% of the human and mouse genomes.
Thymic pDCs express ~22% of their transcriptome from TE sequences.

Quotes

"TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates."
"Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs."
"Strikingly, whereas the percentage of reads from mitochondrial genes was typically lower in pDCs than in other thymic APCs, the proportion of the transcriptome originating from TEs was higher in pDCs (~22%) by several orders of magnitude."

Key Insights Distilled From

Transposable elements regulate thymus development and function

by Larouche,J.-... at www.biorxiv.org 07-14-2023

https://www.biorxiv.org/content/10.1101/2023.07.12.548732v2

Deeper Inquiries

How might the diverse TE expression profiles in thymic cell subsets contribute to the establishment of central tolerance and the prevention of autoimmunity

The diverse expression profiles of transposable elements (TEs) in thymic cell subsets play a crucial role in the establishment of central tolerance and the prevention of autoimmunity. TEs are genetic parasites that make up a significant portion of the genome and are highly expressed in medullary thymic epithelial cells (mTECs) and plasmacytoid dendritic cells (pDCs). In mTECs, TEs interact with transcription factors essential for mTEC development and function, such as PAX1 and REL. These interactions shape complex gene regulatory networks and contribute to the promiscuous expression of tissue-restricted genes, a key process in central tolerance induction. By regulating the expression of TEs, transcription factors like AIRE, FEZF2, and CHD4 control the presentation of self-antigens to developing thymocytes, leading to either deletion of autoreactive T cells or the generation of regulatory T cells (Tregs). This process is essential for educating T cells to distinguish self from non-self, thereby preventing autoimmunity. The mosaic pattern of TE expression in mTECs and the generation of TE-derived MHC-I-associated peptides further contribute to the diversity of the immunopeptidome, shaping the T cell repertoire and ensuring immune tolerance.

What are the potential mechanisms by which TE-derived double-stranded RNAs in thymic pDCs could modulate T cell development and function

TE-derived double-stranded RNAs (dsRNAs) in thymic plasmacytoid dendritic cells (pDCs) have the potential to modulate T cell development and function through their interaction with innate immune receptors. Thymic pDCs express a broad repertoire of TEs, particularly LINEs, LTRs, and SINEs, leading to the formation of dsRNAs. These dsRNAs can activate innate immune sensors like RIG-I and MDA5, triggering the constitutive secretion of interferon alpha (IFN I) and beta (IFN β). The IFN signaling pathway plays a crucial role in regulating the late stages of thymocyte development, promoting the generation of regulatory T cells (Tregs) and innate CD8 T cells. The recognition of TE-derived dsRNAs by innate immune receptors in thymic pDCs creates a pro-inflammatory environment that influences thymocyte education and the shaping of the T cell repertoire. This mechanism highlights the intricate interplay between TEs, innate immunity, and T cell development in the thymus.

Given the importance of the thymic immunopeptidome in shaping the T cell repertoire, how can future studies further elucidate the contribution of TE-derived peptides presented by thymic antigen-presenting cells

Future studies can further elucidate the contribution of TE-derived peptides presented by thymic antigen-presenting cells (APCs) to the immunopeptidome and T cell repertoire through advanced mass spectrometry (MS) techniques and large-scale analyses. By leveraging single-cell RNA-seq data and immunopeptidomic approaches, researchers can identify and characterize TE-derived MHC-I-associated peptides in thymic APC subsets like cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs). These studies can focus on optimizing sample preparation, peptide extraction, and MS analyses to enhance the sensitivity and coverage of TE-derived peptides. Additionally, integrating multi-omic data, including transcriptomic profiles of TE expression and immunopeptidomic data, can provide a comprehensive understanding of how TEs contribute to the immunopeptidome and influence T cell selection in the thymus. By combining cutting-edge technologies and computational analyses, future research can uncover the full extent of TE-derived peptides presented by thymic APCs and their impact on central tolerance and immune homeostasis.