Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

Abstract

The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 regulates NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. In particular, it also modulates IFN-γ production induced by Platelet-Derived Growth Factor (PDGF)-DD following NKp44 engagement. We also show that NID1 may be present at the cell surface. In this form or when bound to a solid support (bNID1), NID1 fails to induce NK cell cytotoxicity or cytokine release. However, analysis by mass spectrometry revealed that exposure to bNID1 can induce in human NK cells relevant changes in the proteomic profiles suggesting an effect on different biological processes.

Mechanisms of Resistance to NK Cell Immunotherapy

“…ii) Tumor cells may also express decoy ligands, capable of inhibiting the signaling of NK cell activating receptors, or even inducing their internalization from the NK cell surface. The soluble form of the extracellular matrix (ECM)-associated nidogen-1 glycoprotein (sNID1) and the β-galactoside binding protein galectin-3 have recently been described as decoy ligands for NKp44 and NKp30, respectively [180,181]. Ligand shedding from the tumor cell surface represents another source of decoy ligands.…”

Natural killer cells: From surface receptors to the cure of high‐risk leukemia (Ceppellini Lecture)

“…It should also be mentioned that soluble NCR ligands have recently been discovered. They include the complement factor P for NKp46, the platelet‐derived growth factor P and Nidogen‐1 for NKp44 . Moreover, NKG2D specifically binds to MICA/B and ULBPs, and DNAM‐1 is specific for poliovirus receptor and nectin‐2, both components of the cellular junctions .…”

“…They include the complement factor P for NKp46, the platelet-derived growth factor P and Nidogen-1 for NKp44. [88][89][90] Moreover, NKG2D specifically binds to MICA/B and ULBPs, and DNAM-1 is specific for poliovirus receptor and nectin-2, both components of the cellular junctions. [91][92][93] The function of these main activating receptors can be amplified by the signaling lymphocyte activation molecule family receptors, whose expression is confined to hematological cells.…”

The yin‐yang of the interaction between myelomonocytic cells and NK cells

“…NCR also interact with soluble ligands with either agonist or antagonist activity. For example, PDGF‐DD and Nidogen‐1 bind to NKp44 inducing NK cell activation and inhibition, respectively . Finally, a role for other activating receptors such as DNAM‐1 belonging to the nectin family and 2B4 belonging to the SLAM family have been also described …”

“…For example, PDGF-DD and Nidogen-1 bind to NKp44 inducing NK cell activation and inhibition, respectively. 17,18 Finally, a role for other activating receptors such as DNAM-1 belonging to the nectin family and 2B4 belonging to the SLAM family have been also described. 4 NK cell inhibitory receptors prevent auto-reactivity while allowing recognition and killing of stressed target cells.…”