Bacterial targeting of the neutrophil inhibitory receptor LILRB3 to evade antibody immunity

Antibody-mediated responses are critical for antibacterial immunity, driving Fc receptor-mediated phagocytosis, respiratory burst, and bacterial killing. Inhibitory immune receptors regulate cellular activation and immune homoeostasis, but whether they are targeted to evade antibody-mediated responses is unclear. Here, we show that the highly expressed inhibitory LILRB3 receptor on neutrophils is targeted by Streptococcus agalactiae to suppress antibody-driven defence. We show that the surface-localised β protein of S. agalactiae bound to LILRB3 and induced its cross-linking. β and LILRB3 interactions suppressed Fc receptor-mediated antibacterial responses such as respiratory burst and bacterial killing, inhibiting antibody-dependent bacterial killing by neutrophils. Moreover, β expression and LILRB3 targeting are associated with S. agalactiae lineages that cause invasive diseases in older adults, indicating that targeting inhibitory receptors most likely provides an immune evasion mechanism when antibody responses are waning, such as in immunocompromised or elderly individuals. Altogether, these results highlight a simple and important mechanism that bacterial pathogens utilise to overcome effective antibody-driven phagocyte responses.