Lessons learned: natural killer cell education as a determinant of the anti-viral functional potential of natural killer cells

A vaccine against the human immunodeficiency virus (HIV) is urgently needed. Recent estimates predict that 34 million people are currently infected with HIV. Attempts to induce potentially protective cytotoxic T-lymphocytes or broadly neutralizing antibodies by vaccination have either proven unsuccessful or failed to elicit the desired immune responses. However, the recent RV144 vaccine trial that provided partial protection against HIV infection appears to have induced antibodies that can utilize cells of the innate immune system, such as natural killer (NK) cells, to mediate antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells. This potential mechanism of protection corroborates recent epidemiological and functional studies demonstrating that HIV-exposed seronegative individuals (HESN) and HIV-infected slow progressors (SP) have higher functioning NK cells and carry certain allelic combinations of killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I (MHC-I or HLA-I) ligands that confer NK cells with enhanced functionality. Cumulatively, these observations suggest that understanding the conferral of functional potential during NK cell ontogeny could be important for designing anti-HIV vaccine constructs. In particular, data from HESN and SP have demonstrated that allelic combinations of KIR3DL1 and its HLA-Bw4 ligand are associated with protective outcomes in the context of HIV. Although previous work has demonstrated thatinteractions between these receptor ligand combinations during NK cell development confers NK cells with functional potential, the exact mechanism of the protective outcomes in the context of HIV remain unknown. For example, KIR3DL1+ NK cells have been demonstrated to be hypofunctional in the presence of autologous HIV-infected T cells. This suggests that if KIR3DL1+ NK cells are providing protection through mediating function, they require additional activating signals. As previously published data has demonstrated that activation through CD16a by antibody constant regions can overcome KIR-mediated NK cell inhibition and lead to ADCC of allogeneic cells, we hypothesized that ADCC could overcome inhibitory signalling and allow KIR3DL1+ NK cells to respond to autologous anti-HIV ADCC target cells. The data presented in this thesis reaffirms that HIV protective KIR3DL1/HLA-Bw4 allelic combinations confer enhanced functional potential upon NK cells. The results presented demonstrate that KIR3DL1/HLA-Bw4 combinations educate NK cells for enhanced anti-HIV ADCC against autologous target cells, and that this educational advantage is maintained after stimulation with function-conferring cytokines, such as IL-15. Furthermore, allelic combinations of KIR3DL1/HLA-Bw4 that are protective in the context of HIV are shown to confer the highest ADCC functional potential. These data suggest that the education of NK cells by allelic combinations of KIR3DL1/HLA-Bw4 could explain some of the protection observed in individuals with these combined genotypes. However, as we also observed anabrogation of this education-conferred functional advantage in HIV-infected individuals, we propose that the mechanisms of NK cell-mediated protection differ between uninfected HESN and infected SP.Not enough spac