The Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway Maintains the Quiescence and Survival of Naive T Cells

Abstract

Naïve T cells receive stimulation from the positive selecting ligand in the periphery for their survival. This stimulation does not normally lead to overt activation of T cells, as the T cells remain largely quiescent until they receive either antigenic or lymphopenic stimuli. The underlying mechanism responsible for survival and quiescence of the naïve T cells remain largely unknown. Here we report that T cell-specific deletion of Tsc1, a negative regulator of mTOR, resulted in both spontaneous losses of quiescence and cellularity, especially within the CD8 subset. The Tsc1-deficient T cells have increased cell proliferation and apoptosis. Tsc1 deletion affects the survival and quiescence of T cells in the absence of antigenic stimulation. Loss of quiescence but not cellularity was inhibited by rapamycin. Our data demonstrate that TSC-mTOR maintains quiescence and survival of T cells.

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

“…Tsc1 is essential to maintain the quiescence of naïve T cells. T-cell-specific deletion of Tsc1 via CD4-Cre mice impairs naïve T-cell survival, homeostasis, and primary immune responses (27)(28)(29). Hence, this mouse model impedes the investigation of Tsc1 functions in antigen-specific effector and memory responses.…”

“…We conclude that Tsc1 is required for the recall response of memory cells upon antigen reexposure. Given the role of Tsc1 in the homeostasis of naïve T cells (27)(28)(29), it remains possible that the T-cell receptor (TCR) repertoire of Tsc1 −/− T cells could be altered and contributed to the defects observed above. We therefore crossed Tsc1 −/− mice onto the TCR-transgenic background (OT-I) in which CD8 + T cells expressed a SIINFEKL peptide-specific TCR.…”

“…Notably, mTOR can be activated by Akt-independent pathways in effector CD8 + T cells (14,25), and deletion of Pten does not cause significant defects in memory formation (23). Here we circumvented the requirements of mTOR signaling in naïve T-cell homeostasis (27)(28)(29) and immediate TCR activation (10), by specific ablation of Tsc1 in antigen-experienced CD8 + T cells. Although Tsc1 deficiency elevates mTORC1 activity, this does not significantly impact the generation of effector CD8 + T cells at the peak phase of primary responses.…”

“…Tuberous sclerosis 1 (Tsc1), a negative regulator of mTORC1 signaling (26), has been implicated in T-cell homeostasis and anergy (27)(28)(29)(30). We and others have demonstrated that deletion of Tsc1 in naïve T cells disrupts their quiescence and survival and dampens T-cell-mediated primary responses to bacterial infection (27)(28)(29).…”

“…We and others have demonstrated that deletion of Tsc1 in naïve T cells disrupts their quiescence and survival and dampens T-cell-mediated primary responses to bacterial infection (27)(28)(29). To circumvent the crucial requirement of Tsc1 in naïve T-cell homeostasis, we developed a mouse model to specifically delete Tsc1 in antigen-experienced CD8 + T cells.…”