The thymus is a primary lymphoid organ that provides a specialized microenvironment for the development and selection of T cells. Thymic epithelial cells (TECs) are the key cellular components of the thymic microenvironment, as they support T cell differentiation, proliferation and survival, and induce central immune tolerance by expressing tissue-restricted antigens (TRAs). Thymic precursor cells differentiate into two major types of thymic epithelial cells (TECs): cortical TECs (cTECs) and medullary TECs (mTECs), which have distinct functions and phenotypes. The development and maturation of TECs are regulated by multiple transcription factors, signaling pathways and epigenetic mechanisms. However, the molecular mechanisms regulating the homeostasis and function of thymic epithelial cells remain incompletely understood. TRAPPC1 (Transport Protein Particle complex 1) is a component of the multi-subunit TRAPP complex which is involved in vesicular transport between the endoplasmic reticulum (ER) and Golgi apparatus. However, recent studies have shown that the intracellular vesicle transport process plays a critical role in the regulation of immune responses. For instance, the intracellular vesicle transport process has been shown to play a role in the regulation of T-cell activation and differentiation. T cells are a type of white blood cell that plays a critical role in the immune system. Previous studies have shown that Trappc1 is essential for embryonic development and hematopoiesis. However, the role of Trappc1 in TEC development and maturation has not been explored before.
In a new report published in the peer-reviewed journal European Journal of Immunology, scientists at the Chinese Academy of Sciences: Dr. Xue Dong, Dr. Zhanfeng Liang, Dr. Jiayu Zhang, Dr. Qian Zhang, Dr. Yanan Xu, Dr. Zhaoqi Zhang, Dr. Lianfeng Zhang, and Dr. Yong Zhao together with Professor Baojun Zhang from Xi’an Jiaotong University discovered a crucial function of Trappc1 in the development and maturation of TECs which provided evidence for the significance of inter-organelle traffic and ER homeostasis in TEC development. By examining TEC-specific homozygous or heterozygous Trappc1 deleted mouse models, the researchers found that Trappc1 deficiency resulted in severe thymus atrophy, reduced cell numbers, and inhibited TEC maturation. As a result, the team engineered mice with TEC-specific Trappc1 deletion to further study Trappc1’s role in TEC development and maturation.
The study revealed that Trappc1 plays a critical role in TEC development, and its deficiency leads to severe thymus atrophy and autoimmune disorders in mice. The researchers found that Trappc1 deficiency in TECs led to reduced TECs numbers, including cortical TECs (cTECs), medullary TECs (mTECs), and common bipotent CD205+ TEC progenitors. The authors noted that Trappc1’s regulatory effect on TEC development was dose-dependent, and increased apoptosis and ferroptosis, rather than altered cell proliferation, caused the decrease of TECs in the Trappc1-deleted mice. The authors’ findings revealed that Trappc1 deficiency in TECs inhibited central immune tolerance establishment and caused autoimmune disorders in mice. The authors noted that Trappc1 deficiency influenced a wide transcriptional program, with the unfolded protein response (UPR) pathway being significantly upregulated. The impaired ER and Golgi homeostasis due to Trappc1 deficiency in TECs caused increased susceptibility to ferroptosis and upregulation of ferroptosis and related metabolic pathways. Interestingly, the increased susceptibility to ferroptosis caused by Trappc1 deletion was restricted to mTECs; cTECs were unaffected, indicating that Trappc1 might regulate mTEC and cTEC development differently. The study also found that Trappc1 deficiency blocked the maturation of mTECs, marked by the decreased expression of CD40, CD80, and MHCII. The percentages of CD80+ and MHCII+ mTECs were significantly decreased in Trappc1 cKO mTECs but not in Trappc1 cHET mTECs. In Trappc1-deleted mTECs, the expression of the transcription factors Irf4, Irf8, and Tbx21 at the mRNA and protein levels was drastically reduced. However, the detailed mechanisms for the impaired mTECs maturation in Trappc1 cKO mice are still an open question, which requires further experimental verification in the future.
To sum up, the authors reported a critical role that Trappc1 plays in the growth and maturation of TECs, as well as in the establishment of central immune tolerance in mice. When Trappc1 is deficient in TECs, it impedes their development and functional maturation by promoting ER-GolgiUPR/ROS-induced apoptosis and ferroptosis. This, in turn, leads to defects in central immune tolerance due to decreased nTreg development and increased poor mTEC TRA expression, which can trigger the development of autoimmune disorders. This elegant study for the first time highlights the importance of inter-organelle traffic and ER homeostasis in TEC development. Further studies are needed to elucidate the molecular mechanisms by which Trappc1 regulates immune responses and its potential as a therapeutic target in the treatment of autoimmune diseases.
Dong X, Liang Z, Zhang J, Zhang Q, Xu Y, Zhang Z, Zhang L, Zhang B, Zhao Y. Trappc1 deficiency impairs thymic epithelial cell development by breaking endoplasmic reticulum homeostasis. European Journal of Immunology. 2022 Nov;52(11):1789-804.