KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-γ-mediated effects

• Published in: Molecular immunology Vol. 115; pp. 39 - 55
• Main Authors: Banerjee, P.P., Pang, L., Soldan, S.S., Miah, S.M., Eisenberg, A., Maru, S., Waldman, A., Smith, E.A., Rosenberg-Hasson, Y., Hirschberg, D., Smith, A., Ablashi, D.V., Campbell, K.S., Orange, J.S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2019
• Subjects: Cell Line; Cytotoxicity, Immunologic - immunology; Demyelination; HLA-G Antigens - immunology; Humans; Interferon-gamma - immunology; Killer Cells, Natural - immunology; Multiple sclerosis; Multiple Sclerosis - immunology; Myelin protein; Myelin-Associated Glycoprotein - immunology; Natural killer cell; Oligodendrocyte; Oligodendroglia - immunology; Receptors, KIR2DL4 - immunology; Receptors, Natural Killer Cell - immunology; RG-KIR2DL4; WT-KIR2DL4; Multiple sclerosis; MOG; MS; eNK cell; HLAG; KIR2DL1; Myelin protein; KIR2DL4; IFN; Natural killer cell; MAG; Oligodendrocyte; Demyelination; OL
• ISSN: 0161-5890; 1872-9142; 1872-9142
• DOI: 10.1016/j.molimm.2018.09.027

•NK cell KIR2DL4 interacts with HLA-G on OLs, leading to IFN-γ production by NK cells.•IFN-γ from NK cells reduces myelin protein content from OLs in vitro.•KIR2DL4+ and CD56bright NK cells are higher in number in MS patients.•Patient NK cell-OL conjugates are high in IFN-γ but low in myelin protein content. Interactions between germline-encoded natural killer (NK) cell receptors and their respective ligands on tumorigenic or virus-infected cells determine NK cell cytotoxic activity and/or cytokine secretion. NK cell cytokine responses can be augmented in and can potentially contribute to multiple sclerosis (MS), an inflammatory disease of the central nervous system focused upon the oligodendrocytes (OLs). To investigate mechanisms by which NK cells may contribute to MS pathogenesis, we developed an in vitro human model of OL-NK cell interaction. We found that activated, but not resting human NK cells form conjugates with, and mediate cytotoxicity against, human oligodendrocytes. NK cells, when in conjugate with OLs, rapidly synthesize and polarize IFN-γ toward the OLs. IFN-γ  is capable of reducing myelin oligodendrocyte and myelin associated glycoproteins (MOG and MAG) content. This activity is independent of MHC class-I mediated inhibition via KIR2DL1, but dependent upon the interaction between NK cell-expressed KIR2DL4 and its oligodendrocyte-expressed ligand, HLA-G. NK cells from patients with MS express higher levels of IFN-γ following conjugation to OLs, more actively promote in vitro reduction of MOG and MAG and have higher frequencies of the KIR2DL4 positive population. These data collectively suggest a mechanism by which NK cells can promote pathogenic effects upon OLs.