title: Activating and inhibitory Ly49 receptors modulate NK cell chemotaxis to CXC chemokine ligand (CXCL) 10 and CXCL12.
abstract: NK cells can migrate into sites of inflammatory responses or malignancies in response to chemokines. Target killing by rodent NK cells is restricted by opposing signals from inhibitory and activating Ly49 receptors. The rat NK leukemic cell line RNK16 constitutively expresses functional receptors for the inflammatory chemokine CXC chemokine ligand (CXCL)10 (CXCR3) and the homeostatic chemokine CXCL12 (CXCR4). RNK-16 cells transfected with either the activating Ly49D receptor or the inhibitory Ly49A receptor were used to examine the effects of NK receptor ligation on CXCL10- and CXCL12-mediated chemotaxis. Ligation of Ly49A, either with Abs or its MHC class I ligand H2-D(d), led to a decrease in chemotactic responses to either CXCL10 or CXCL12. In contrast, Ly49D ligation with Abs or H2-D(d) led to an increase in migration toward CXCL10, but a decrease in chemotaxis toward CXCL12. Ly49-dependent effects on RNK-16 chemotaxis were not the result of surface modulation of CXCR3 or CXCR4 as demonstrated by flow cytometry. A mutation of the Src homology phosphatase-1 binding motif in Ly49A completely abrogated Ly49-dependent effects on both CXCL10 and CXCL12 chemotaxis, suggesting a role for Src homology phosphatase-1 in Ly49A/chemokine receptor cross-talk. Ly49D-transfected cells were pretreated with the Syk kinase inhibitor Piceatannol before ligation, which abrogated the previously observed changes in migration toward CXCL10 and CXCL12. Piceatannol also abrogated Ly49A-dependent inhibition of chemotaxis toward CXCL10, but not CXCL12. Collectively, these data suggest that Ly49 receptors can influence NK cell chemotaxis within sites of inflammation or tumor growth upon interaction with target cells.
authors.affiliation: Department of Arthritis and Immunology, Veterans Affairs Medical Center, Northern California Institute for Research and Education, and University of California, San Francisco, CA 94121, USA. marit.inngjerdingen@basal.uio.no
authors.forename: Marit
authors.initials: M
authors.lastname: Inngjerdingen
authors.forename: Bent
authors.initials: B
authors.lastname: Rolstad
authors.forename: James C
authors.initials: JC
authors.lastname: Ryan
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002464:Cell Migration Inhibition; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003432:Cross-Linking Reagents / Q000378:metabolism; D004792:Enzyme Precursors / Q000502:physiology; D006183:H-2 Antigens / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D055630:Receptors, NK Cell Lectin-Like; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D000950:Antigens, Ly; C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003432:Cross-Linking Reagents; C515189:Cxcr3 protein, rat; D004792:Enzyme Precursors; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat