Priming of Qualitatively Superior Human Effector CD8+ T Cells Using TLR8 Ligand Combined with FLT3 Ligand

Abstract

The quality of Ag-specific CD8+ T cell responses is central to immune efficacy in infectious and malignant settings. Inducing effector CD8+ T cells with potent functional properties is therefore a priority in the field of immunotherapy. However, the optimal assessment of new treatment strategies in humans is limited by currently available testing platforms. In this study, we introduce an original model of in vitro CD8+ T cell priming, based on an accelerated dendritic cell coculture system, which uses unfractionated human PBMCs as the starting material. This approach enables the rapid evaluation of adjuvant effects on the functional properties of human CD8+ T cells primed from Ag-specific naive precursors. We demonstrate that a selective TLR8 agonist, in combination with FLT3L, primes high-quality CD8+ T cell responses. TLR8L/FLT3L-primed CD8+ T cells displayed enhanced cytotoxic activity, polyfunctionality, and Ag sensitivity. The acquisition of this superior functional profile was associated with increased T-bet expression induced via an IL-12–dependent mechanism. Collectively, these data validate an expedited route to vaccine delivery or optimal T cell expansion for adoptive cell transfer.