377 Critical Role of NKp44L, the Ligand of the Activated Natural Cytotoxicity Receptor NKp44 in the CD4+ T-cells Depletion During HIV Infection V. Viellard*1, J. L. Strominger2, P. Debré1 1INSERM U543, Hosp Pitié-Salpétrière, Paris, France and 2Harvard Univ, Cambridge, MA
Background: Natural killer (NK) cells participate in the innate immune responses against HIV. The ability of NK cells to kill virus-infected cells is regulated by a balance between inhibitory and activating receptors. A novel emerging group of receptors, the natural cytotoxicity receptors (NCRs) are responsible for NK cell-triggering in an HLA-independent context. As compared of the other NCRs, NKp44 is specifically expressed in activated NK cells. NKp44L, the cellular ligand of NKp44, recently cloned by us, is a novel glycoprotein expressed in several stress situations.
Methods: Blood samples were collected from 20 HIV- individuals and 25 HIV+ patients at different stages of HIV infection. Cell surface expression of NKp44L was analyzed using 3-color flow cytometric analysis. Engagement of NKp44L during the NK lysis process was evaluated using a standard 51Cr release assay.
Results: In PBMC from HIV- donors the expression of NKp44L was closed to the background before or after PHA-activation. In contrast, in HIV+ patients, NKp44L was specifically expressed on CD4+ T-cells (between 3% to 32% of CD4+ T-cells). Any significant expression was detected on CD8+ T-cells or CD3- cells. This expression was correlated with the level of CD4+ T-cells and the viral load. Furthermore, after PHA-activation, the level of NKp44L was strongly increased in CD4+ T-cells from HIV-infected patients. Phenotypically, the NKp44L+ cells expressed several activated markers and were more susceptible to apoptosis. Concomitantly, the NK receptor NKp44 was specifically expressed during HIV infection. As compared to NKp44L- cells, the NKp44L+ cells were strongly more susceptible to the NK lysis against autologous NK cells. This NK lysis was blocked with a treatment of NK cells by an excess of anti-NKp44 mAb.
Conclusions: The specific expression of NKp44L by the CD4+ T-cells in HIV+ individuals, as a function of disease evolution, and it’s relationship with NK cell lysis, suggested that activated NK cells could be implicate in the CD4+ T-cell depletion during HIV infection.
