Curtailed T-cell activation curbs effector differentiation and generates CD8T cells with a naturally-occurring memory stem cell phenotype

Research output: Contribution to journalArticle

Abstract

Human T memory stem (TSCM) cells with superior persistence capacity and effector functions are emerging as important players in the maintenance of long-lived T-cell memory and are thus considered an attractive population to be used in adoptive transfer-based immunotherapy of cancer. However, the molecular signals regulating their generation remain poorly defined. Here we show that curtailed T-cell receptor stimulation curbs human effector CD8+T-cell differentiation and allows the generation of CD45RO-CD45RA+CCR7+CD27+CD95+-phenotype cells from highly purified naïve T-cell precursors, resembling naturally-occurring human TSCM. These cells proliferate extensively in vitro and in vivo, express low amounts of effector-associated genes and transcription factors and undergo considerable self-renewal in response to IL-15 while retaining effector differentiation potential. Such a phenotype is associated with a lower number of mitochondria compared to highly-activated effector T cells committed to terminal differentiation. These results shed light on the molecular signals that are required to generate long-lived memory T cells with potential application in adoptive cell transfer immunotherapy.

Original languageEnglish
Pages (from-to)1468-1476
Number of pages9
JournalEuropean Journal of Immunology
Volume47
Issue number9
DOIs
Publication statusPublished - Sep 2017

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Keywords

  • Adult Stem Cells
  • Animals
  • Antigens, CD
  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines
  • Cell Differentiation
  • Cell Proliferation
  • Cell Self Renewal
  • Cells, Cultured
  • Humans
  • Immunologic Memory
  • Immunophenotyping
  • Immunotherapy, Adoptive
  • Interleukin-15
  • Lymphocyte Activation
  • Mice
  • Mice, SCID
  • Neoplasms
  • Phenotype
  • Receptors, Antigen, T-Cell
  • Journal Article
  • Research Support, Non-U.S. Gov't

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