Natural killer cell regulation of HIV vaccine responses

Abstract

Abstract Understanding mechanisms that regulate humoral responses are crucial for the design of more efficacious vaccines. We have previously shown that natural killer (NK) cells suppress antiviral T-cell function and antibody production during acute virus infection in mice. NK cells also inhibited follicular helper (TFH) T-cell and germinal center (GC) B-cell responses following immunization with an alum-adjuvanted, non-replicating hapten-protein, NP-KLH. In addition, the frequency and type of mutations observed during SHM in NP-specific GC B cells is linked to NK cells, demonstrating that NK cells are important modulators of not just the quantity, but also the quality of the humoral response. To test the impact of NK cells on clinically-relevant HIV vaccine regimens, mice were depleted of NK cells prior to administration of an HIV envelope-expressing vaccinia virus vector. When NK cells were absent during priming, vaccine-induced TFH and GC B cell responses were increased along with production of HIV-specific immunoglobulin. Using a prime-boost vaccination scheme, we observed that NK cells also suppressed recall responses of B cells, such that combined depletion during both prime and boost immunizations had an enhanced effect on humoral responses. These results demonstrate that NK cells are important inhibitory regulators of affinity maturation and HIV-specific humoral responses, such that NK cells may limit vaccine-mediated generation of broadly neutralizing antibodies by curtailing GC responses. These data demonstrate the exciting potential to manipulate NK cells in order to promote effective vaccine-elicited protection against HIV infection.