Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages

Area of Science:

• Immunology
• Developmental Biology
• Genomics

Background:

• Central tolerance induction relies on interactions between T cells and Aire+ medullary thymic epithelial cells (mTECs).
• Thymocytes regulate mTEC cellularity, but their control over mTEC precursors remains unclear.
• Recent single-cell transcriptomics identified diverse mTEC subsets, including mTEC low (mTEC^lo) populations.

Purpose of the Study:

• To investigate whether thymocytes control mTEC^lo subsets, which are precursors to Aire⁺ mTEC^hi cells.
• To elucidate the molecular mechanisms by which T cell-mTEC interactions shape mTEC heterogeneity.
• To determine the role of these interactions in preventing autoimmunity.

Main Methods:

• Utilized three transgenic mouse models with perturbed antigen presentation between mTECs and CD4+ thymocytes.
• Performed high-throughput RNA-sequencing (RNA-seq) to analyze transcriptional changes in mTECs.
• Assessed histone modifications (H3K4me3) and immune responses.

Main Results:

• Self-reactive CD4+ T cells induce transcriptional regulators in mTEC^lo cells.
• These interactions control the composition of mTEC^lo subsets, including precursors for Aire⁺ mTEC^hi, post-Aire, and tuft-like mTECs.
• Upregulation of tissue-restricted antigens, cytokines, chemokines, adhesion molecules, and H3K4me3 marks in mTECs was observed.
• Self-reactive T cell-mTEC interactions were shown to prevent multiorgan autoimmunity.

Conclusions:

• Self-reactive CD4+ T cells exert significant control over immature mTEC populations, influencing their differentiation and heterogeneity.
• These interactions are essential for establishing central tolerance and preventing autoimmune diseases.
• The study reveals novel regulatory roles of T cells in early mTEC development.