Role of the Notch-TRIB2 axis in CD8+ T cell differentiation

Abstract

Abstract Following activation, naïve CD8+ T cells expand and differentiate into two effector subpopulations: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). After the effector response has taken place, SLECs undergo apoptosis, while MPECs mature into memory T cells that protect against reinfection. Notch, a highly conserved pathway, was shown to control SLEC differentiation. Our transcriptomic analysis has revealed that Notch signalling controls the transcription of a large number of genes in activated CD8+ T cells. Among them is Trib2, coding for the pseudokinase Tribbles homolog 2. TRIB2 was reported to activate AKT in some tumour cell lines while Notch-deficient CD8+ T cells show decreased AKT activation, suggesting that Notch transcriptional induction of Trib2 might be important to properly activate AKT and promote SLEC differentiation. Therefore, we hypothesize that induction of TRIB2 expression by Notch signalling promotes SLEC differentiation through AKT activation. To test this, we overexpressed TRIB2 in Notch1–2 deficient CD8+ T cells using retroviral transduction and followed their differentiation after their adoptive transfer into Listeria infected mice. Our results show that overexpression of TRIB2 partially restores SLEC generation in absence of Notch. In conclusion, we uncovered that TRIB2 promotes SLEC differentiation through the Notch pathway. These findings provide a better understanding of the molecular events controlling the differentiation of SLECs, a cell type essential for the elimination of infected cells and cancer.