Natural killer cells suppress humoral immunity and development of neutralizing antibodies (VIR1P.962)

Abstract

Abstract Pathogen-specific neutralizing antibodies (nAbs) are a key component of protective immunity after infection or vaccination. However, broadly-specific nAbs that can prevent infections with highly mutable viruses like HIV are rarely seen in infected patients and are poorly elicited by current vaccines. Therefore, new vaccine strategies are needed to enhance the induction of nAbs, potentially by augmenting the germinal center (GC) reactions that facilitate somatic hypermutation, affinity maturation and development of high-affinity nAbs. Here, we demonstrate that natural killer (NK) cells impair humoral immunity by contributing to a weak GC response and subdued generation of virus-specific nAbs after acute lymphocytic choriomeningitis virus (LCMV) infection of mice. The magnitude and duration of the LCMV-induced GC response was substantially reduced by NK cells, which constricted the number of both follicular helper T cells (Tfh) and GC B cells present in lymphoid tissues. NK cell-mediated suppression of GC responses was also observed in different stains of mice and after infection with a variety of dissimilar pathogens, suggesting that NK cell suppression of humoral immunity is a universal feature of infection. Notably, NK cell inhibition of the GC response during LCMV infection resulted in a markedly delayed and relatively weak nAb response. Thus, targeting of immunosuppressive NK cells could represent a revolutionary method to enhance the efficacy of future vaccine regimens.