Journal
BLOOD ADVANCES
Volume 4, Issue 16, Pages 3990-4006Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2020002084
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Funding
- Intramural Research Program of the National Institutes of Health (National Cancer Institute, Center for Cancer Research, Cancer and Inflammation Program) [1ZIABC011152]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/54599-5, 2011/05331-0, 2012/23478-0, 2014/10290-9, 2017/13686-9]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- National Institutes of Health, National Institute of Allergy and Infectious Diseases grant [R01AI120989, R01AI137275]
- American Society for Hematology Junior Scholar award
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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.
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