FOXO1 opposition of CD8+ T cell effector programming confers early memory properties and phenotypic diversity

Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):E8865-E8874. doi: 10.1073/pnas.1618916114. Epub 2017 Oct 2.


The factors and steps controlling postinfection CD8+ T cell terminal effector versus memory differentiation are incompletely understood. Whereas we found that naive TCF7 (alias "Tcf-1") expression is FOXO1 independent, early postinfection we report bimodal, FOXO1-dependent expression of the memory-essential transcription factor TCF7 in pathogen-specific CD8+ T cells. We determined the early postinfection TCF7high population is marked by low TIM3 expression and bears memory signature hallmarks before the appearance of established memory precursor marker CD127 (IL-7R). These cells exhibit diminished TBET, GZMB, mTOR signaling, and cell cycle progression. Day 5 postinfection, TCF7high cells express higher memory-associated BCL2 and EOMES, as well as increased accumulation potential and capacity to differentiate into memory phenotype cells. TCF7 retroviral transduction opposes GZMB expression and the formation of KLRG1pos phenotype cells, demonstrating an active role for TCF7 in extinguishing the effector program and forestalling terminal differentiation. Past the peak of the cellular immune response, we report a gradient of FOXO1 and TCF7 expression, which functions to oppose TBET and orchestrate a continuum of effector-to-memory phenotypes.

Keywords: CD8+ T cell; host; immune memory; immunology; pathogen.

Publication types

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

MeSH terms

  • Animals
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / physiology*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Granzymes / genetics
  • Granzymes / metabolism
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Hepatitis A Virus Cellular Receptor 2 / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / immunology
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Immunologic Memory / physiology*
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Lectins, C-Type
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Receptors, Immunologic / metabolism


  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Interleukin-7 Receptor alpha Subunit
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Receptors, Immunologic
  • Granzymes
  • Gzmb protein, mouse