Hosp Clin Porto Alegre, Cellular Technol & Therapy Ctr, Porto Alegre, RS - Brazil
 Columbia Univ, Dept Pediat, Irving Med Ctr, New York, NY - USA
 Univ Sao Paulo, Cell & Mol Therapy Ctr NETCEM, Sao Paulo - Brazil
Total Affiliations: 9
AUG 25 2020.
Web of Science Citations:
Adaptive immune responses are acknowledged to evolve from innate immunity. However, limited information exists regarding whether encounters between innate cells direct the generation of specialized T-cell subsets. We aim to understand how natural killer (NK) cells modulate cell-mediated immunity in humans. We found that human CD14(+)CD16(-) monocytes that differentiate into inflammatory dendritic cells (DCs) are shaped at the early stages of differentiation by cell-to-cell interactions with NK cells. Although a fraction of monocytes is eliminated by NK-cell-mediated cytotoxicity, the polarization of interferon-gamma (IFN-gamma) at the NKp30-stabilized synapses triggers a stable IFN-gamma signature in surviving monocytes that persists after their differentiation into DCs. Notably, NK-cell-instructed DCs drive the priming of type 17 CD8(+) T cells (Tc17) with the capacity to produce IFN-gamma and interleukin-17A. Compared with healthy donors, this cellular network is impaired in patients with classical NK-cell deficiency driven by mutations in the GATA2 gene. Our findings reveal a previously unrecognized connection by which Tc17-mediated immunity might be regulated by NK-cell-mediated tuning of antigen-presenting cells. (AU)