title: Anti-HIV antibody-dependent activation of NK cells impairs NKp46 expression.
abstract: There is much interest in the potential of Ab-dependent cellular cytotoxicity (ADCC) to slow disease progression following HIV infection. Despite several studies demonstrating a positive association between ADCC and slower disease progression, it is possible that continued stimulation of NK cells by ADCC during chronic HIV infection could render these cells dysfunctional. Indeed, activation of NK cells by ADCC results in matrix metalloproteinase-induced reductions in CD16 expression and activation refractory periods. In addition, ex vivo analyses of NK cells from HIV-infected individuals revealed other alterations in phenotype, such as decreased expression of the activating NKp46 receptor that is essential for NK-mediated antitumor responses and immunity from infection. Because NKp46 shares a signaling pathway with CD16, we hypothesized that activation-induced downregulation of both receptors could be controlled by a common mechanism. We found that activation of NK cells by anti-HIV or anti-CD16 Abs resulted in NKp46 downregulation. The addition of a matrix metalloproteinase inhibitor attenuated NKp46 downregulation following NK cell activation by anti-HIV Abs. Consequently, these results suggest that continued stimulation through CD16 has the potential to impair natural cytotoxicity via attenuation of NKp46-dependent signals.
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Matthew S
authors: MS
authors: Parsons
authors: Chi-Chang
authors: CC
authors: Tang
authors: Sinthujan
authors: S
authors: Jegaskanda
authors: Robert J
authors: RJ
authors: Center
authors: Andrew G
authors: AG
authors: Brooks
authors: Ivan
authors: I
authors: Stratov
authors: Stephen J
authors: SJ
authors: Kent
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D015483:HIV Antibodies; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D017452:Receptors, IgG; D020782:Matrix Metalloproteinases