Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs

Abstract

Significance Enhancing the generation and function of memory T cells represents a crucial strategy to improve protective immunity against pathogens and tumors. The signaling pathway via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells, but the upstream regulators or downstream mechanisms remain unclear. In this study, we provide insight into the mechanistic basis that controls mTOR signaling and memory T-cell responses. The deficiency of tuberous sclerosis 1 (Tsc1) in antigen-experienced T cells impairs the differentiation of memory T-cell precursors and the formation of memory T cells, associated with excessive mTOR activity and dysregulated cell metabolism. Our study establishes a molecular mechanism that links mTOR signaling and cell metabolism for memory T-cell development.

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

“…The mTORC1 complex is identified as a protein complex containing the scaffolding protein Raptor and is activated by the small GTPase Rheb (15,16). Previous studies have shown mTORC1 as a crucial regulator of CD8 T cell effector function and memory (17)(18)(19). We show that with Ag-specific stimulation, engagement of TIM-3 on CD8 T cells promotes effector function through mTORC1 signaling correlating with increased expression of rhebl1, whose gene product is an isoform of mTOR activator Rheb (15,16,20).…”

T cell metabolism drives immunity

“…Innate immune receptor activation increases intracellular succinate from glutamine via glutamine-dependent anerplerosis and the -aminobutyric acid shunt pathway, and this leads to HIF-1 stabilization and activation (Tannahill et al, 2013). During glycolytic transcriptional program initiated by c-Myc to support T cell population expansion (Chou et al, 2014;Karmaus and Chi, 2014). HIF-1, a transcription factor that responds to oxygen levels, also increases glucose uptake and catabolism through glycolysis (Kim et al, 2006;Finlay et al, 2012).…”

“…Inhibiting mTOR with rapamycin boosts memory T cell development in vivo (Araki et al, 2009;Pearce et al, 2009;Rao et al, 2010). Loss of the mTORC1-negative regulator TSC1 compromises formation of memory T cell precursors that are present during the primary effector response (Kaech et al, 2003;Shrestha et al, 2014). Similarly, suppressing mTORC2 fosters memory T cell generation (Pollizzi et al, Review histone acetylation after antigen-driven stimulation (Avni et al, 2002;Fields et al, 2002).…”

Multiple Players in the Mechanical Control of T Cell Quiescence

“…Tsc1 is important in T cell biology in memory cell differentiation, effector, and regulatory functions [53,54]. Tsc1 is also implicated in anergy T cells, and its expression is higher in anergy as compared to activated T cells [55].…”