Curtailed T-cell activation curbs effector differentiation and generates CD8+ud T cells with a naturally-occurring memory stem cell phenotype

摘要

Human T memory stem (TudSCMud) cells with superior persistence capacity and effectorudfunctions are emerging as important players in the maintenance of long-lived T-celludmemory and are thus considered an attractive population to be used in adoptiveudtransfer-based immunotherapy of cancer. However, the molecular signals regulatingudtheir generation remain poorly defined. Here we show that curtailed T-cell receptorudstimulation curbs human effector CD8ud+udT-cell differentiation and allows the genera-udtion of CD45ROud–udCD45RAud+udCCR7ud+udCD27ud+udCD95ud+ud-phenotype cells from highly purified na ̈udıveudT-cell precursors, resembling naturally-occurring human TudSCMud. These cells proliferateudextensively in vitro and in vivo, express low amounts of effector-associated genes andudtranscription factors and undergo considerable self-renewal in response to IL-15 whileudretaining effector differentiation potential. Such a phenotype is associated with a lowerudnumber of mitochondria compared to highly-activated effector T cells committed to ter-udminal differentiation. These results shed light on the molecular signals that are requiredudto generate long-lived memory T cells with potential application in adoptive cell transferudimmunotherapy.