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 (tRNASec) required for translation of all selenoproteins. In this study, we found that Trsp was required for thymopoiesis, with the majority of tRNASec-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 in vitro and Treg-specific Trsp deletion using Trspfl/flFoxp3YFP-Cre (TrspDTreg) mice caused fatal autoimmunity similar to FOXP3-deficient mice. Reducing oxidative stress via 2-HOBA administration prolonged survival in these TrspDTreg mice. These findings indicate that tRNASec is required for T cell homeostasis and may be therapeutic targets in inflammation or carcinoma.