The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin

Immunity. 2010 Jan 29;32(1):67-78. doi: 10.1016/j.immuni.2009.10.010. Epub 2010 Jan 7.

Abstract

The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways. Blocking mTOR activity by rapamycin reversed IL-12-induced effector functions because of loss of persistent expression of the transcription factor T-bet. Rapamycin treatment of IL-12-conditioned OT-I cells promoted persistent Eomesodermin expression and produced memory cell precursors that demonstrated enhanced sustenance and antigen-recall responses upon adoptive transfer. The memory cell precursors showed greater tumor efficacy than IL-12-conditioned effector OT-I cells. These results identify mTOR as the central regulator of transcriptional programs that determine effector and/or memory cell fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell-mediated immunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology*
  • Immunologic Memory / immunology
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / immunology
  • T-Box Domain Proteins / biosynthesis
  • T-Box Domain Proteins / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • TOR Serine-Threonine Kinases
  • Transduction, Genetic

Substances

  • Eomes protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases