IL‐15 and CD155 expression regulate LAT expression in murine DNAM1⁺ NK cells, enhancing their effectors functions

Abstract

NK cells are innate immune cells characterized by their ability to spontaneously lyse tumor and virally infected cells. We have recently demonstrated that IL‐15‐sufficient DC regulate NK cell effector functions in mice. Here, we established that among ITAM‐proximal signaling molecules, the expression levels of the scaffold molecule Linker for Activation of T cells (LAT) and its transcription factor ELF‐1 were reduced 4 days after in vivo depletion of DC. Addition of IL‐15, a cytokine presented by DC to NK cells, regulates LAT expression in NK cells with a significant effect on the DNAM1+ subset compared to DNAM1− cells. We also found that LAT expression is regulated via interaction of the DNAM1 receptor with its ligand CD155 in both immature and mature NK cells, independently of NK cell education. Finally, we found that LAT expression within DNAM1+ NK cells might be responsible for enhanced calcium mobilization following the triggering of activating receptors on NK cells. Altogether, we found that LAT expression is tightly regulated in DNAM1+ NK cells, via interaction(s) with DC, which express CD155 and IL‐15, resulting in rapid activation of the DNAM1+ subset during activating receptor triggering.

FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development

“…We next assessed NK cell maturation in the three FOXO-deficient mouse strains based on CD11b and CD27 expression ( 49 , 50 ). In this scheme, the first stage of NK cell maturation is characterized by low expression of both CD27 and CD11b (CD27 low CD11b low ).…”

Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

“…One possibility is that DCs produce the chemokines that attract NK cells, thus facilitating physical interaction. Once DCs and NK cells are in close proximity, DC-derived IL-12 or IL-15 presented by DCs could lead to the increased effector functions and proliferation [84]. The ability to interact with cognate MHC-I, together with higher levels of the adhesion receptor DNAM-1 on educated NK cells [85], could facilitate or prolong the interaction between DCs and NK cells, which would lead to a preferential presentation of IL-15 to specifically educated NK cells, explaining the increased proliferation of these subsets.…”

SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency

“…Intracellular antibody staining was performed with antibodies against IFN-γ, SHP-1, SHP-2, and SHIP1 (see data file S1 for more information) with the Foxp3/Transcription Factor Staining Buffer Kit (eBiosciences). The intracellular staining procedure was performed as described previously ( 79 ). Data were acquired on an LSR Fortessa or a Symphony flow cytometer (BD Biosciences) and analyzed with FlowJo v9.9.6 or v10.7.1 software (TreeStar).…”