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.
Curtailed T-cell activation curbs effector differentiation and generates CD8(+) T cells with a naturally-occuring memory stem cell phenotype / V. Zanon, K. Pilipow, E. Scamardella, F. De Paoli, G. De Simone, D.A. Price, A. Martinez Usatorre, P. Romero, D. Mavilio, A. Roberto, E. Lugli. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 47:9(2017 Sep), pp. 1468-1476. [10.1002/eji.201646732]
Curtailed T-cell activation curbs effector differentiation and generates CD8(+) T cells with a naturally-occuring memory stem cell phenotype
V. ZanonPrimo
;D. Mavilio;
2017
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.File | Dimensione | Formato | |
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