S100A9 protein is a novel ligand for the CD85j receptor and its interaction is implicated in the control of HIV-1 replication by NK cells.

International audienceBACKGROUND: The reportedly broad expression of CD85j across different immune cell types suggests an importance for this molecule in the human immune system. Previous reports have shown that this receptor interacts with several HLA class-I molecules, as well as with some viral proteins. We have demonstrated that the subset of CD85j + Natural Killer (NK) cells efficiently controls human immunodeficiency virus type 1 (HIV-1) replication in monocyte-derived dendritic cells (MDDC) in vitro and this led us to hypothesize that the CD85j + NK cell-mediated anti-HIV activity in MDDC is specifically dependent on the interaction between the CD85j receptor and unknown non-HLA class-I ligand(s). RESULTS: In this study, we focused our efforts on the identification of these non-described ligands for CD85j. We found that the CD85j receptor interacts with a calcium-binding proteins of the S100 family; namely, S100A9. We further demonstrated that HIV-1 infection of MDDC induces a modulation of S100A9 expression on surface of the MDDC, which potentially influences the anti-HIV-1 activity of human NK cells through a mechanism involving CD85j ligation. Additionally, we showed that stimulation of NK cells with exogenous S100A9 enhances the control of HIV-1 infection in CD4+ T cells. CONCLUSIONS: Our data show that S100A9 protein, through ligation with CD85j, can stimulate the anti-HIV-1 activity of NK cells

Natural killer cell responses to dendritic cells infected by the ANRS HIV-1 vaccine candidate, MVA HIV

International audienceInnate mechanisms are critical for the development of the host immune responses to antigen. Particularly, early interaction between natural killer (NK) cells and dendritic cells (DC) greatly impacts the establishment of both innate and adaptive immune responses. In this study, using an autologous in vitro co-culture system we analyzed the NK cell response against MVAHIV-infected DC as well as the subsequent ability of these MVAHIV-primed NK cells to control HIV-1 infection in autologous DC. We found that NK cells responded early to MVAHIV- or MVAWT-infected DC in terms of degranulation and cytokine production. After a 4-day priming of NK cells by MVAHIV- or MVAWT-infected DC we observed an enhanced proliferation and modulation in the NK cell receptor repertoire expression. Interestingly, we found that MVAHIV-primed NK cells had a significant higher ability to control HIV-1 infection in autologous DC compared to MVAWT-primed NK cells; and this enhanced anti-HIV-1 activity appeared to be HIV-specific as MVAHIV-primed NK cells did not have a better ability to control other viral infections or respond against tumoral cells. Furthermore, we observed that NK cell receptors NKG2D and NKp46 modulate the priming of NK cells. This data provides evidence that in vitro NK cells can be primed by viral vector-infected DC, in the context of a NK/DC culture, to specifically target viral infected cells

Dynamic Shift from CD85j/ILT-2 to NKG2D NK Receptor Expression Pattern on Human Decidual NK during the First Trimester of Pregnancy

International audienceDuring the first trimester of human pregnancy, Natural Killer (NK) cells of the maternal uterine mucosa (e.g. decidua) have a unique phenotype and are involved in crucial physiological processes during pregnancy. We investigated whether modifications of the NK receptor repertoire occur during the first trimester of pregnancy. We found significantly decreased expression of KIR2DL1/S1 and KIR2DL2/L3/S2 receptors, NKp30 and NKp44 activatory receptors, and the CD85j (ILT-2) inhibitory receptor. We also observed significantly increased expression of the NKG2D activatory receptor at the decidual NK cell surface. By flow cytometry, we further highlighted an evolution of NK subsets between 8 and 12 weeks of gestation, with a shift from the KIR2DL1/S1 + /KIR2DL2/L3/S2 + subset towards the double negative subset, coupled with a decrease of the CD85j + /NKG2D 2 subset in favour of the CD85j 2 /NKG2D + subset. Furthermore, cell surface expression of NK receptor ligands, including CD85j and NKG2D ligands, has been characterized by flow cytometry on decidual immune CD14 + and CD3 + cells. HLA-G, the high affinity ligand of CD85j, was detected on both cell types. In contrast, NKG2D ligands ULBP-2 ULBP-3 and MICA/B were not expressed on CD14 + and CD3 + cells, however a variable expression of ULBP-1 was observed. The ligand expression of KIR2DL1/S1 and KIR2DL2/L3/S2 was also analyzed: the HLA-C molecule was expressed at a low level on some CD14 + cells whereas it was not detected on CD3 + cell surface. NK receptor ligands are known to be also expressed on the invading placental trophoblast cells. Thus, the phenotypic evolutions of decidual NK cells described in this present study may preserve their activation/inhibition balance during the first trimester of pregnancy

Evolution of the CD85j - NKG2D dNK subset during the first trimester of pregnancy.

<p>Decidual mononuclear cells were analyzed by flow cytometry immediately after isolation. The dNK cells were defined by the CD3⁻/CD56⁺ population within the decidual cells. (A) CD85j and NKG2D co-expression was analyzed on samples taken at 57 days (early, red), 63 days (middle, blue) and 78 days of gestation samples (late, green). Representative donor analyses are shown individually and overlaid (right dot plot). (B) Linear regression for each subset, percentage within the dNK cells (Y) and day of gestation (X). The analyses were performed on decidual cells from 28 different donors, individually represented by a dot.</p

Spearman correlation coefficient (p-value) of surface expression between NK receptors (n = 28).

<p>*Bold data are statistically significant (p-value ≤0.004).</p

NK receptor repertoire evolution of dNK cells during the first trimester of pregnancy.

<p>Expression of NK receptors on decidual mononuclear cells was analyzed between 8 and 12 weeks of gestation. Graphs represent the percentage of marker expression (Y) and the day of gestation (X). The line represents the linear regression. A p-value<0.05 was significant. The analyses were performed on decidual cells from 28 different donors, individually represented by a dot.</p