Endoplasmic reticulum associated degradation adaptor Sel1L regulates T cell survival and homeostasis

Abstract

Abstract Suppressor/Enhancer of Lin-12-like (Sel1L) acts as a critical adaptor in endoplasmic reticulum-associated degradation (ERAD), a process that maintains cellular protein quality control through the degradation of misfolded proteins. Here, we investigate the role of Sel1L in mature T cells. CD4Cre-driven deletion of Sel1L in murine models resulted in a slight decrease in the frequency and absolute number of CD4 and CD8 single-positive thymocytes with a profound reduction in peripheral T cells. Using mixed bone marrow chimeras, Sel1L regulates peripheral T cell survival in a cell-intrinsic manner. Sel1L-deficient T cells have increased AnnexinV staining suggesting Sel1L deletion promotes apoptosis. Furthermore, the Sel1L conditional knockout mice have a marked defect in the naïve CD8+ T cell compartment, which also occurs in a cell-intrinsic manner. These data suggest that Sel1L is critical for the maintenance of naïve CD8+ T cell homeostasis. Sel1L-deficient T cells exhibit enhanced mTORC1 activation with increased cellular phosphorylated S6 ribosomal protein and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (4-EBP1), as well as altered cellular metabolism. These results identify a novel role for Sel1L in T cell survival and homeostasis.