SEL1L preserves CD8+ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis

SEL1L-mediated endoplasmic reticulum-associated degradation (ERAD) plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins. However, it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis. Herein, we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells, which was further validated by adoptive transfer experiments or bone marrow chimera experiments, accompanied by the induction of multiple forms of cell death. Furthermore, SEL1L deficiency selectively disrupted naive CD8(+) T-cell homeostasis, as indicated by the severe loss of the naive T-cell subset but an increase in the memory T-cell subset. We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift, which was largely attributable to enhanced expression of the IL-15 receptor alpha and beta chains. Mechanistically, single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l(-/-) CD8(+) T cells harbored excessive ER stress, particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway, which was alleviated by supplementing IL-7 or IL-15. Importantly, PERK inhibition greatly resolved the survival defects of Sel1l(-/-) CD8(+) T cells. In addition, IRE1 alpha deficiency decreased mTORC1 signaling in Sel1l(-/-) naive CD8(+) T cells by downregulating the IL-15 receptor alpha chain. Altogether, these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.

Automated summary

Studies have shown that SEL1L deficiency leads to reduced frequency and number of peripheral T cells, especially naive CD8(+) T cells. SEL1L deficiency also results in activation of mTORC1/c-MYC and metabolic shift, as well as excessive endoplasmic reticulum stress. These findings suggest that SEL1L plays an important role in preserving the survival and homeostasis of peripheral T cells.