期刊
JOURNAL OF IMMUNOLOGY
卷 189, 期 7, 页码 3299-3310出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1102495
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资金
- Ministerio de Educacion y Competitividad [TRA2009_0030, SAF2011-22831]
- Fondo de Investigacion Sanitaria [PI11/02327]
- Departamento de Salud (Gobierno de Navarra)
- Union Temporal de Empresas Project Centre for Applied Medical Research
- Digna-Biotech
- Asociacion Espanola Contra el Cancer
- MEC [RYC-2007-00928]
Previous mouse and human studies have demonstrated that direct IFN-alpha/beta signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-alpha possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-alpha are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-alpha-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-alpha during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-alpha exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-alpha during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy. The Journal of Immunology, 2012, 189: 3299-3310.
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