Browsing by Subject "Receptors, KIR"

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    A Genome-Wide CRISPR/Cas9-Based Screen Identifies Heparan Sulfate Proteoglycans as Ligands of Killer-Cell Immunoglobulin-Like Receptors.
    (Frontiers in immunology, 2021-01) Klein, Klara; Hölzemer, Angelique; Wang, Tim; Kim, Tae-Eun; Dugan, Haley L; Jost, Stephanie; Altfeld, Marcus; Garcia-Beltran, Wilfredo F
    While human leukocyte antigen (HLA) and HLA-like proteins comprise an overwhelming majority of known ligands for NK-cell receptors, the interactions of NK-cell receptors with non-conventional ligands, particularly carbohydrate antigens, is less well described. We previously found through a bead-based HLA screen that KIR3DS1, a formerly orphan member of the killer-cell immunoglobulin-like receptor (KIR) family, binds to HLA-F. In this study, we assessed the ligand binding profile of KIR3DS1 to cell lines using Fc fusion constructs, and discovered that KIR3DS1-Fc exhibited binding to several human cell lines including ones devoid of HLA. To identify these non-HLA ligands, we developed a magnetic enrichment-based genome-wide CRISPR/Cas9 knock-out screen approach, and identified enzymes involved in the biosynthesis of heparan sulfate as crucial for the binding of KIR3DS1-Fc to K562 cells. This interaction between KIR3DS1 and heparan sulfate was confirmed via surface plasmon resonance, and removal of heparan sulfate proteoglycans from cell surfaces abolished KIR3DS1-Fc binding. Testing of additional KIR-Fc constructs demonstrated that KIR family members containing a D0 domain (KIR3DS1, KIR3DL1, KIR3DL2, KIR2DL4, and KIR2DL5) bound to heparan sulfate, while those without a D0 domain (KIR2DL1, KIR2DL2, KIR2DL3, and KIR2DS4) did not. Overall, this study demonstrates the use of a genome-wide CRISPR/Cas9 knock-out strategy to unbiasedly identify unconventional ligands of NK-cell receptors. Furthermore, we uncover a previously underrecognized binding of various activating and inhibitory KIRs to heparan sulfate proteoglycans that may play a role in NK-cell receptor signaling and target-cell recognition.
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    Eighth Annual International Umbilical Cord Blood Transplantation Symposium, San Francisco, California, June 3-5, 2010.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2011-02) Laughlin, Mary; Kurtzberg, Joanne; McMannis, John; Petz, Lawrence
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    NK cell education: Physiological and pathological influences.
    (Frontiers in immunology, 2023-01) Rascle, Philippe; Woolley, Griffin; Jost, Stephanie; Manickam, Cordelia; Reeves, R Keith
    Natural killer (NK) cells represent a critical defense against viral infections and cancers. NK cells require integration of activating and inhibitory NK cell receptors to detect target cells and the balance of these NK cell inputs defines the global NK cell response. The sensitivity of the response is largely defined by interactions between self-major histocompatibility complex class I (MHC-I) molecules and specific inhibitory NK cell receptors, so-called NK cell education. Thus, NK cell education is a crucial process to generate tuned effector NK cell responses in different diseases. In this review, we discuss the relationship between NK cell education and physiologic factors (type of self-MHC-I, self-MHC-I allelic variants, variant of the self-MHC-I-binding peptides, cytokine effects and inhibitory KIR expression) underlying NK cell education profiles (effector function or metabolism). Additionally, we describe the broad-spectrum of effector educated NK cell functions on different pathologies (such as HIV-1, CMV and tumors, among others).