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

Justin Jacobse, Jennifer M Pilat, Anna Brooke Harris, Aaron Kwag, Zaryab Aziz, Channing Chi, Sam Schaefer, M Diana Neely, Matthew A Buendia, Andrew Pahnke, …
bioRxiv
Cold Spring Harbor Laboratory
09/15/2025
DOI: 10.1101/2025.09.09.675163
PMCID: PMC12458461
PMID: 41000784
url
https://doi.org/10.1101/2025.09.09.675163View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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 !ιTreg ) mice caused fatal autoimmunity similar to FOXP3-deficient mice. Reducing oxidative stress via 2-HOBA administration prolonged survival in these Trsp !ιTreg mice. These findings indicate that tRNA Sec is required for T cell homeostasis and may be therapeutic targets in inflammation.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 !ιTreg ) mice caused fatal autoimmunity similar to FOXP3-deficient mice. Reducing oxidative stress via 2-HOBA administration prolonged survival in these Trsp !ιTreg mice. These findings indicate that tRNA Sec is required for T cell homeostasis and may be therapeutic targets in inflammation.Trsp , a gene required for translation of all selenoproteins, is essential for all T cell development and function, especially regulatory T cells.One sentence summaryTrsp , a gene required for translation of all selenoproteins, is essential for all T cell development and function, especially regulatory T cells.

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