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 language | English |
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Pages (from-to) | 1468-1476 |
Number of pages | 9 |
Journal | European Journal of Immunology |
Volume | 47 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sep 2017 |
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