Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 47, Issue 9, Pages 1468-1476Publisher
WILEY
DOI: 10.1002/eji.201646732
Keywords
Adoptive cell transfer; CD8(+); Effector T cells; T-cell activation; T memory stem cells
Categories
Funding
- European Research Council (ERC-StG PERSYST) [640511]
- Fondazione Cariplo (Grant Ricerca Biomedica) [2012/0683]
- Italian Ministry of Health (Bando Giovani Ricercatori) [GR-2011-02347324]
- European Union Marie Curie Career Integration [322093]
- Fondazione Italiana per la Ricerca sul Cancro (FIRC)
- European Research Council (ERC) [640511] Funding Source: European Research Council (ERC)
- Wellcome Trust [100326/Z/12/Z] Funding Source: researchfish
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Human T memory stem (T-SCM) 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 naive T-cell precursors, resembling naturally-occurring human T-SCM. 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.
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