Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β-selection.

Abstract

Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4^-CD8^-double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of <i>Sel1l</i> impaired DN3 to DN4 thymocyte transition and severely impaired mouse αβ T cell development. Mechanistically, <i>Sel1l</i> deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from <i>Sel1l</i>-deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate <i>Sel1l</i>-deficiency-induced ER stress. Dual loss of <i>Sel1l</i> and <i>Xbp1</i> markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.