Tmed4, also known as transmembrane p24 trafficking protein 4, is an endoplasmic reticulum stress (ERS)-related protein. It is involved in maintaining regulatory T cell (Treg) stability and function, potentially through protein vesicular trafficking and antioxidant response pathways [1,2]. Tmed4 plays a crucial role in biological processes related to immune regulation and may impact various disease conditions.

In Treg-specific knockout (Tmed4ΔTreg) mice, loss of Tmed4 led to more Tregs with impaired Foxp3 stability, Treg signatures, and suppressive activity. This caused T cell hyperactivation, an exacerbated inflammatory phenotype, and boosted antitumor immunity. Mechanistically, Tmed4 deficiency caused defects in ERS and the NRF2-related antioxidant response, resulting in excessive ROS that reduced Treg function in an IRE1α/XBP1 axis-dependent manner. These abnormalities could be rescued by a ROS scavenger, NRF2 inducer, or forced expression of IRE1α. Also, TMED4 suppressed IRE1α proteosome degradation via the ER-associated degradation (ERAD) system [1].

In conclusion, Tmed4 is essential for maintaining the stability of Tregs and their suppressive function through the IRE1α-dependent ROS and NRF2-related antioxidant response. The Tmed4ΔTreg mouse model has revealed its significance in tumor and autoimmune disease conditions, contributing to our understanding of immune-related disease mechanisms [1].