Trsp is required by regulatory T cells to prevent lethal autoimmunity in mice

Selenoproteins are involved in immune cell metabolism, yet the roles of these proteins in T cell development and function remain largely unknown. The Trsp gene encodes the selenocysteine tRNA (tRNA^Sec) required for translation of all selenoproteins. In this study, we found that Trsp was required for thymopoiesis, with the majority of tRNA^Sec-deficient T cells not progressing beyond double negative 3 stage, with egressed thymocytes undergoing peripheral homeostatic expansion. Trsp-deficient CD4⁺ T cells exhibited impairments in TCR and IL-2 signaling and did not cause inflammation in experimental models. On the other hand, Trsp-deficient regulatory T (Treg) cells exhibited defects in suppressive function ex vivo and Treg-specific Trsp deletion using Trsp ^fl/fl Foxp3 ^YFP-Cre (Trsp ^ΔTreg) mice caused fatal autoimmunity similar to FOXP3-deficient mice. Reducing oxidative stress via 2-HOBA administration prolonged survival in these Trsp ^ΔTreg mice. These findings indicate that tRNA^Sec is required for T cell homeostasis and may be therapeutic targets in inflammation.