Natural killer T (NKT)–B-cell interactions promote prolonged antibody responses and long-term memory to pneumococcal capsular polysaccharides

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (40), p.16097-16102
• Main Authors: Li Bai, Deng, Shenglou, Reboulet, Rachel, Mathew, Rebecca, Teytone, Luc, Savage, Paul B., Bendelac, Albert
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - immunology; Antigens; B lymphocytes; B-Lymphocytes - immunology; Biological Sciences; Carbohydrates; Cell Communication - immunology; Cell Differentiation - immunology; Cells; Flow Cytometry; Immunologic Memory - immunology; Isotypes; Lipids; Liposomes; Memory; Mice; Mice, Inbred C57BL; Nanoparticles - administration & dosage; Natural killer T cells; Natural Killer T-Cells - immunology; Pneumococcal Infections - immunology; Polysaccharides; Polysaccharides, Bacterial - administration & dosage; Polysaccharides, Bacterial - immunology; Statistics, Nonparametric; Streptococcus pneumoniae; T lymphocytes; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1303218110

Innate-like natural killer T (NKT) cells critically enhance cell and humoral immunity against infections through recognition of conserved microbial lipid antigens presented by CD1d-expressing antigen-presenting cells, and provision of CD40L and cytokine signals. Whereas NKT cells efficiently licensed dendritic cells to prime potent effector and memory T cells, studies based on model antigens such as alphagalactosylceramide-nitrophenyl conjugates concluded that help to B cells was associated with NKT follicular helper differentiation, but limited to short-term responses without induction of memory. We revisited this surprising conclusion in the context of the extracellular encapsulated pathogen Streptococcus pneumoniae , where recognition of lipid and capsular polysaccharide antigens by NKT cells and B cells, respectively, provide critical host protection. Using liposomal nanoparticles displaying synthetic lipid and polysaccharide antigens to elicit pure and direct NKT–B-cell interactions in vivo, we observed intense and prolonged antibody responses with isotype switch, affinity maturation, and long-lasting B-cell memory, despite modest or absent NKT follicular helper differentiation. Furthermore, conditional ablation of Cd1d demonstrated a requirement for a two-step process involving first cognate interactions with dendritic cells, for NKT cell activation, and then with B cells, for induction of isotype switch and memory. Thus, NKT help to B cells represents both a major arm of antimicrobial defense and a promising target for B-cell vaccines.