HIV Infection Abrogates the Functional Advantage of Natural Killer Cells Educated through KIR3DL1/HLA-Bw4 Interactions To Mediate Anti-HIV Antibody-Dependent Cellular Cytotoxicity

Parsons, Matthew S.; Wren, Leia; Isitman, Gamze; Navis, Marjon; Stratov, Ivan; Bernard, Nicole F.; Kent, Stephen J.

doi:10.1128/jvi.06112-11

Cited by 45 publications

(67 citation statements)

References 35 publications

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“…This possibility is concordant with the epidemiological observation that SPs have higher frequencies of inhibitory KIR3DL1/HLA-Bw4 ligand combinations than do individuals with more rapidly progressing infections (45). It was demonstrated that these KIR/HLA combinations increase the functional potential of NK cells during the ontological process of NK cell education (46,47) and that this education results in higher anti-HIV ADCC against autologous targets (48). Furthermore, an additional study (49) demonstrated that NK cells carrying KIR3DL1 are expanded in primary HIV infection.…”

Section: Discussionsupporting

confidence: 78%

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

Parsons

Tang

Jegaskanda

et al. 2014

The Journal of Immunology

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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.

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Section: Discussionsupporting

confidence: 78%

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

Parsons

Tang

Jegaskanda

et al. 2014

The Journal of Immunology

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“…1 NK cells from HLA-Bw4-carrying uninfected donors, no longer exhibit higher antibody-dependent function than the KIR3DL1 2 subset [20]. The data presented in Fig.…”

Section: Discussionmentioning

confidence: 71%

“…Lastly, we also predicted that the heightened function of educated NK cells, defined as those expressing the inhibitory killer immunoglobulin-like receptor 3DL1 (KIR3DL1) that recognizes a self major histocompatibility complex class I (MHC-I or HLA-I) molecule containing the human leucocyte antigen (HLA)-Bw4 ligand, would result in lower levels of CD16 expression post-activation than those exhibited by the KIR3DL1 2 NK cell subset, which contains non-educated NK cells and NK cells educated through alternative inhibitory receptor/ ligand combinations [19][20][21]. We utilized two previously described assays to measure antibody-dependent activation of NK cells [16], and now present data illustrating a role for the degree of NK cell activation on post-activation CD16 cleavage.…”

Section: Cd107amentioning

confidence: 99%

“…The potential of NK cells to mediate both antibody-dependent and -independent functions is determined during the ontological process of education, where NK cells expressing inhibitory receptors that recognize self HLA-I ligands acquire the ability to respond upon receipt of a cumulative activating signal [19][20][21]. Previous work from our group and others has shown educated NK cells to be more primed to mediate antibody-dependent activation than noneducated NK cells [19][20][21]. As such, the observation of lower CD16 expression on the most highly activated NK cells suggests that decreased CD16 expression occurs most prominently on educated NK cells.…”

Section: Post-activation Cd16 Expression On Educated Nk Cellsmentioning

confidence: 99%

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Phenotypical and functional profiles of natural killer cells exhibiting matrix metalloproteinase-mediated CD16 cleavage after anti-HIV antibody-dependent activation

Tang

Isitman

Bruneau

et al. 2015

Clinical and Experimental Immunology

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SummaryNatural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been linked to protection from HIV infection and slower progression towards AIDS. However, antibody-dependent activation of NK cells results in phenotypical alterations similar to those observed on NK cells from individuals with progressive HIV infection. Activation of NK cells induces matrix metalloproteinase (MMP)-mediated cleavage of cell surface CD16. In the present study we assessed the phenotype and functional profile of NK cells exhibiting post-activation MMP-mediated CD16 cleavage. We found that NK cells achieving the highest levels of activation during stimulation exhibit the most profound decreases in CD16 expression. Further, we observed that educated KIR3DL1

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“…NK cells from all 9 HIV negative donors expressed IFNγ when incubated in the presence of HIV+ plasma. It is of interest to note that the responses were not of a uniform magnitude, suggesting there may be other phenotypic features within individuals that influence these responses such as KIR phenotype 23 or FcR polymorphism. 24 We previously showed that HIV-antibody specific IFNγ expression by NK cells correlates with NK cell degranulation as assessed by the marker CD107a and granzyme B loss, 13 however we have not previously identified the cell targets being killed by ADCC in this whole blood assay.…”

Section: Discussionmentioning

confidence: 99%