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In vitro generation of mature, naive antigen-specific CD8 + T cells with a single T-cell receptor by agonist selection

par Snauwaert, Sylvia;Verstichel, Greet;Bonte, S.;Goetgeluk, Glenn;Vanhee, Stijn;van Caeneghem, Yasmine;De Mulder, Katrien;Heirman, Carlo;Stauss, H.;Heemskerk, Mirjam;Taghon, Tom;Leclercq, Georges ;Plum, Jean;Langerak, Anton;Thielemans, Kris M.;Kerre, Tessa;Vandekerckhove, Bart
Référence Leukemia, 28, 4, page (830-841)
Publication Publié, 2014

Article révisé par les pairs

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Résumé :

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 multimer-reactive 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. ? 2014 Macmillan Publishers Limited.