期刊
LEUKEMIA
卷 28, 期 4, 页码 830-841出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.285
关键词
T lymphopoiesis; adoptive cellular immunotherapy; hematopoietic progenitor cell; OP9-DL1; antigen-specific T cell
资金
- Research Foundation - Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, FWO)
- Stichting tegen Kanker
- geconcerteerde onderzoeksactiviteiten of Ghent University
- Interuniversity Attraction Poles Program
- Belgian Science Policy
- Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen
- Research Foundation-Flanders (FWO)
- MRC [G0900950] Funding Source: UKRI
- Medical Research Council [G0900950] Funding Source: researchfish
Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8(+) T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4(+)CD8(+) double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8(+) T cells. comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8(+) T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimerreactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing.
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