Trappc1 deficiency impairs thymic epithelial cell development by breaking endoplasmic reticulum homeostasis

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Thymic epithelial cells (TECs) are vital for T cell development and immune tolerance.
• The molecular mechanisms governing TEC development are extensively studied, but the role of transport protein particle complexes (Trappcs) remains unclear.

Purpose of the Study:

• To investigate the function of Trappc1 within TECs.
• To elucidate the molecular pathways affected by Trappc1 deficiency in TECs.

Main Methods:

• Utilized TEC-specific homozygous or heterozygous Trappc1 deleted mice models.
• Performed RNA-sequencing and molecular analyses.
• Assessed thymus cellularity, TEC maturation, T cell output, and autoimmune phenotypes.

Main Results:

• Trappc1 deficiency caused severe thymus atrophy, reduced TEC numbers, and blocked TEC maturation.
• Mice exhibited poor thymic T cell output, increased activated/memory T cells, and spontaneous autoimmune disorders.
• Molecular studies revealed decreased endoplasmic reticulum (ER) and Golgi, enhanced unfolded protein response (UPR), ER-stress-induced apoptosis, and ferroptosis in Trappc1-deficient TECs.

Conclusions:

• Trappc1 is essential for TEC development, maturation, and homeostasis.
• ER and Golgi dysfunction, coupled with UPR and ferroptosis, contribute to TEC reduction.
• Impaired expression of Aire and associated transcription factors in Trappc1-deficient mTECs may affect tissue-restricted antigen presentation.