Abstract
Natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d protein. The initial discovery of immunostimulatory glycolipids from a marine sponge and the T cells that respond to the compounds has led to extensive research by chemists and immunologists to understand how glycolipids are recognized, possible responses by NKT cells, and the structural features of glycolipids necessary for stimulatory activity. The presence of this cell type in humans and most mammals suggests that it plays critical roles in antigen recognition and the interface between innate and adaptive immunity. Both endogenous and exogenous natural antigens for NKT cells have been identified, and it is likely that glycolipid antigens remain to be discovered. Multiple series of structurally varied glycolipids have been synthesized and tested for stimulatory activity. The structural features of glycolipids necessary for NKT cell stimulation are moderately well understood, and designed compounds have proven to be much more potent antigens than their natural counterparts. Nevertheless, control over NKT cell responses by designed glycolipids has not been optimized, and further research will be required to fully reveal the therapeutic potential of this cell type.
Highlights
Natural killer T (NKT) cells are a subset of T cells that recognize a variety of lipid and glycolipid antigens
Similar to the amide- and urea-linked analogs, the triazole-linked compounds demonstrated biasing towards either a T helper 1 (TH1) and, in one case, a T helper 2 (TH2) response. These results show that subtle differences at the 6"-position can impart large differences in iNKT cell stimulation
Identification of natural antigens has focused on endogenous and exogenous antigens, and it is likely that many of these have yet to be discovered. iNKT cell selection and iNKT cell autoreactivity argue for endogenous antigens, and these may play a key roles in regulating both innate and adaptive immune responses
Summary
Natural killer T (NKT) cells are a subset of T cells that recognize a variety of lipid and glycolipid antigens. In contrast to T-helper cells and cytotoxic T cells, the TCR of iNKT cells recognizes antigens that are presented by the non-classical MHC-like membrane-bound cell-surface glycoprotein CD1d [5,6]. Presented antigenic lipids or glycolipids interact with the TCR of iNKT cells and this interaction subsequently activates iNKT cells, releasing a variety of cytokines and chemokines that modulate and/or stimulate the immune system [2,15]. Released cytokines can activate adaptive cells, such as T and B cells, and innate cells, such as dendritic cells and NK cells [20,21] These bidirectional signals can be received through cell surface receptors, such as the TCR recognizing lipid-bound CD1, costimulatory receptors (CD40, CD70, OX40), or cytokines. Because of their immunological role, governing the stimulation of iNKT cells is a therapeutically relevant goal
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