Curtailed T-cell activation curbs effector differentiation and generates CD8⁺ T cells with a naturally-occurring...

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 naïve 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.