Open AccessDifferential IL-12 signaling induces human natural killer cell activating receptor-mediated ligand-specific expansion
Author(s) -
Avishai Shemesh,
Harry Pickering,
Kole T. Roybal,
Lewis L. Lanier
Publication year - 2022
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20212434
Subject(s) - microbiology and biotechnology , interleukin 15 , biology , interleukin 21 , interleukin 12 , stat5 , downregulation and upregulation , signal transduction , janus kinase 3 , natural killer cell , t cell , cancer research , cytokine , immunology , interleukin , immune system , cytotoxic t cell , in vitro , biochemistry , gene
IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12-dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12-dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2-primed NK cell-based therapies.