The Influence of Invariant Natural Killer T Cells on Humoral Immunity to T-Dependent and -Independent Antigens

Abstract

Vaccination with CD1d-binding glycolipid adjuvants and co-administered protein, lipid, and carbohydrate antigens leads to invariant natural killer T (NKT) cell-dependent enhancement of protective B cell responses. NKT cell activation boosts the establishment of protein antigen-specific B cell memory and long-lived plasma cell (LLPC) compartments. NKT cells may exert a similar effect on some carbohydrate-specific B cells, but not lipid-specific B cells. The mechanisms of action of NKT cells on B cell responsiveness and subsequent differentiation into memory B cells and LLPC is dependent on CD1d expression by dendritic cells and B cells that can co-present glycolipids on CD1d and antigen-derived peptide on MHCII. CD1d/glycolipid-activated NKT cells are able to provide help to B cells in a manner dependent on cognate and non-cognate interactions. More recently, a glycolipid-expanded subset of IL-21-secreting NKT cells known as NKT follicular helper cells has been suggested to be a driver of NKT-enhanced humoral immunity. This review summarizes established and recent findings on how NKT cells impact humoral immunity and suggests possible areas of investigation that may allow the incorporation of NKT-activating agents into vaccine adjuvant platforms.

Keywords: CD1d; Natural Killer T; humoral immunity; pathogen; vaccine.

Figure 1

Model for natural killer T (NKT) cell influence on humoral immunity (A) CD1d^+/+ dendritic cells (DCs) are able to capture, internalize, process, and present peptide Ag on MHCII and glycolipid Ag on CD1d and do so in a coordinated fashion. As a result, Th cell priming occurs, as does NKT activation and/or NKT follicular helper cell (NKTfh) differentiation. (B) B cells capture Ag via the BCR, but also capture complexed CD1d-binding glycolipid, or internalize it by endocytosis. B cells are, thus, able to coordinately present peptide on MHCII and glycolipid on CD1d. Consequently, B cells are able to receive help from DC primed or activated classical Th/Tfh cells as well as NKT/NKTfh cells. The additional help from NKT/NKTfh cells enhances the establishment of a Bmem compartment and the generation of long-lived plasma cells.