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

5 years ago

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

Federica Paoli, Eloise Scamardella, Enrico Lugli, Veronica Zanon, Domenico Mavilio, Pedro Romero, Gabriele Simone, Amaia Martinez Usatorre, David A. Price, Alessandra Roberto, Karolina Pilipow

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. T memory stem cells (TSCM) with increased persistence are most suitable cell type for adoptive cell transfer immunotherapy. Weak TCR stimulation of human naïve CD8+ T cells induces a CD45RO– CD45RA+ TSCM phenotype. The proliferating TSCM display decreased T-cell activation, effector molecules and mitochondrial content compared to more differentiated T effectors.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/eji.201646732