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.

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

“…However, unlike Tfh-derived B cell responses, those driven by NKTfh cells have no potential to generate long-lived plasma cells and memory B cells ( 196 ). NKTfh cells also possess the ability to boost memory B cell responses to T-dependent antigens but not T-independent lipid antigens ( 198 ). In addition, the NKTfh cells can induce limited GC B cell responses in the absence of CD4 + cell help ( 199 ).…”

CAR‐T cell therapy in melanoma: A future success story?

“…[85,86] Natural killer T (NKT) cells, which share characteristics of natural killer (NK) cells and T cells, represent an effective cell subpopulation in pathogen and tumor cell defense. [87,88] The high number and functionality of NKT cells in blood or tumor was demonstrated to directly correlate with better survival in different human cancers. [88] The advantage of NKT cells over conventional T cells may be their pronounced intrinsic anti-tumor activity through their endogenous TCR [88,89] and is triggered by glycolipids presented via CD1d on antigen-presenting cells.…”

Functions of CD1d-Restricted Invariant Natural Killer T Cells in Antimicrobial Immunity and Potential Applications for Infection Control

“…Glycolipid-mediated i NKT cell activation also augments antibody production by B cells ( 58 , 59 ). Intranasal administration of α-GalCer and influenza hemagglutinin (HA) vaccine or formalin-inactivated whole-virion vaccine induced higher titers of mucosal IgA and systemic IgG compared to influenza vaccine alone ( 60 – 62 ).…”

“…Although it is well known that follicular helper T (T FH ) cells play a critical role in the stimulation of germinal center B cells for high-affinity antibody production, as well as differentiation of memory B cells and long-lived plasma cells, recent studies have demonstrated that follicular helper NKT (NKT FH ) cells contribute to augmented IgG antibody production by vaccines containing an i NKT cell glycolipid antigen ( 59 , 64 – 67 ). Immunization of mice with liposomes containing pneumococcal capsular polysaccharide (CPS) and PBS57, an α-GalCer analog, or CPS-α-GalCer conjugate vaccine induced NKT FH cells expressing PD-1 and CXCR5 or PD-1 and ICOS ( 66 , 67 ).…”