Natural Killer cell-mediated antibody-dependent cellular cytotoxicity towards red blood cells infected by Plasmodium falciparum

Abstract

Abstract In areas of high Plasmodium transmission, humans develop clinical immunity only after years of recurrent exposure. This naturally acquired immunity depends primarily on antibodies specific for parasite antigens. The underlying basis of this protective response remains unclear. In particular, the contribution of antibody-dependent cellular cytotoxicity (ADCC) to malaria immunity remains largely unexplored. Peripheral blood natural killer (NK) cells exhibit potent ADCC through FcγRIII (CD16) binding to antibody-coated target cells. We have developed sensitive and quantitative in vitro assays to evaluate outcome of infected red blood cells (RBC) incubation with NK cells. Without specific antibodies, NK cell-mediated natural cytotoxicity was undetectable towards both uninfected and infected RBCs. Addition of serum antibodies raised against human RBCs in immunized rabbits, however, produced NK cell-dependent lysis of both uninfected and infected RBCs. Rabbit serum antibodies specific for PfEMP1, an immunodominant P. falciparum variant antigen at the surface of infected RBCs, yielded selective lysis of infected RBCs. Plasma from malaria-immune individuals also triggered selective NK-mediated ADCC of infected RBCs. Finally, incubation of infected RBCs with NK cells in the presence of plasma from malaria-immune individuals inhibited P. falciparum growth, as determined by reinvasion of fresh, uninfected RBCs. Therefore, primary human NK cells can limit growth of bloodstream P. falciparum through specific ADCC-mediated lysis of infected RBCs.