The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function

Nat Immunol. 2011 Jul 17;12(9):888-97. doi: 10.1038/ni.2068.

Abstract

The mechanisms that regulate T cell quiescence are poorly understood. We report that the tumor suppressor Tsc1 established a quiescence program in naive T cells by controlling cell size, cell cycle entry and responses to stimulation of the T cell antigen receptor. Abrogation of quiescence predisposed Tsc1-deficient T cells to apoptosis that resulted in loss of conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells had more activity of the serine-threonine kinase complex mTORC1 but less mTORC2 activity, and activation of mTORC1 was essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in actively maintaining the quiescence of naive T cells to facilitate adaptive immune function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Apoptosis
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Cycle / immunology
  • Cell Survival / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Homeostasis
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Multiprotein Complexes
  • Proteins / genetics
  • Proteins / immunology*
  • Proteins / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / immunology*
  • TOR Serine-Threonine Kinases
  • Trans-Activators / genetics
  • Trans-Activators / immunology*
  • Trans-Activators / metabolism
  • Transcription Factors
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins* / deficiency
  • Tumor Suppressor Proteins* / genetics
  • Tumor Suppressor Proteins* / immunology

Substances

  • Crtc2 protein, mouse
  • Multiprotein Complexes
  • Proteins
  • RNA, Messenger
  • Reactive Oxygen Species
  • Trans-Activators
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1

Associated data

  • GEO/GSE29797