Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Medullary thymic epithelial cells (mTECs) are crucial for establishing self-tolerance through promiscuous expression of tissue-restricted antigens (TRAs).
• The mosaic expression pattern of TRAs, where each antigen is present in only a small subset of mTECs, is a key feature but its single-cell mechanism remains unclear.

Purpose of the Study:

• To elucidate the single-cell mechanisms underlying the mosaic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs).
• To investigate the coexpression patterns of genes within mTECs and their relationship to TRA expression.

Main Methods:

• Analysis of gene coexpression patterns in subsets of human mTECs expressing specific TRAs.
• Identification of gene clusters and their chromosomal mapping.
• Investigation of mTEC differentiation stages and in vitro interconversion of TRA subsets.

Main Results:

• Subsets of human mTECs expressing specific TRAs exhibited distinct coexpression gene profiles.
• Three coexpression groups were identified, with overlapping and complementary gene sets preferentially mapping to specific chromosomes and intrachromosomal clusters.
• Coexpressed gene loci were found to colocalize within the same nuclear subdomain, and TRA subsets aligned with progressive mTEC differentiation stages, showing in vitro interconversion.

Conclusions:

• Single mTECs dynamically shift through distinct gene pools, facilitating the scanning of a broad repertoire of promiscuously expressed self-antigens.
• These findings provide insights into the temporal and spatial presentation of self-antigens in the thymus, impacting self-tolerance induction.