CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

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Natural Killer T cells are a distinct lymphocyte lineage that regulates a broad range of immune responses. NKT cells recognize glycolipids presented by the non-classical MHC molecule CD1d. Structural insight into the TCR/glycolipid/CD1d tri-complex has revealed an unusual and unexpected mode of recognition. Recent studies have also identified some of the signaling events during NKT cell development that give NKT cells their innate phenotype. Pathogen-derived glycolipid antigens continue to be found, and new mechanisms of NKT cell activation have been described. Finally, NKT cells have been shown to be remarkably versatile in function during various immune responses. Whether these extensive functional capacities can be attributed to a single population sensitive to environmental cues or if functionally distinct NKT cell subpopulations exist remains unresolved.

Introduction

Roughly two decades ago, a unique T lymphocyte population was identified in both mice and humans. These cells were referred to as natural killer T cells (NKT cells) owing to their co-expression of phenotypic markers usually found on T and natural killer (NK) cells. Since their discovery, several aspects of the biology of these cells have been uncovered. Not only has the phenotype of these cells been more fully characterized, details of their unique ontogeny and development have started to emerge. In addition, several antigens have been identified and we are beginning to understand how these antigens are recognized by NKT cells. To date, NKT cells have been reported to be critical in the regulation of many different types of immune responses, ranging from self-tolerance and development of autoimmunity to responses to pathogens and tumors. However, it remains unclear how NKT cells conceivably play such apparently diverse roles from one type of immune response to another. With this in mind, we will highlight recent advances in the study of NKT cell function, outlining what is now known about how NKT cells can be activated and what the outcome of their activation on the immune response can be.

Section snippets

What is an NKT cell?

The original definition of NKT cells as T lymphocytes co-expressing an αβ T cell antigen receptor (TCR) and NK cell receptors now represents an oversimplification and is a poor definition. While it is true that the vast majority of NKT cells express NK receptors, other, unrelated T cell populations, such as activated conventional CD8 T cells, can also express them. Furthermore, the expression of NK receptors by NKT cells varies with their developmental stage, their activation state and, at

What does it take to make an iNKT cell?

iNKT cells develop in the thymus [4]. They are absent from nude mice, do not develop in thymectomized mice, and first appear in the thymus slightly later than conventional T cells. The unusual phenotype and functional attributes of iNKT cells suggested that they likely derived from a particular developmental program. Originally, two models were proposed to account for the development of this unique lymphocyte population. The first model hypothesized that iNKT cells derive from a pre-committed

What can iNKT cells do?

Perhaps the single most confounding issue in understanding and predicting iNKT cell function in vivo is the fact that iNKT cells have been shown to do so many different kinds of things during an immune response. Not only do they have the capacity to rapidly and robustly produce cytokines and chemokines, they also have the ability, as their name would suggest, to kill other cells (Figure 1A). In addition, they have been shown to influence the behavior of many other immune cells (Figure 1B). In

What antigens do iNKT cells recognize?

The first described iNKT cell ligand was α-Galactosylceramide (α-Galcer), which was identified from a panel of marine extracts for its anti-tumor activity [62]. Since then, many more iNKT cell antigens have been discovered, including both endogenous and exogenous antigens. Unlike conventional T cell antigens that are predominantly peptides presented by MHC molecules, iNKT cell antigens have a distinct lipid component to them. Most iNKT antigens defined to date share a common structure: a lipid

How do iNKT cells recognize their antigens?

The unique antigen specificity of iNKT cells is dictated by the expression of the semi-invariant TCR. How this TCR, which was known to have a similar overall structure to known peptide/MHC-reactive TCRs, might instead recognize glycolipid antigens in the context of CD1d was the subject of constant speculation. Recent crystallographic success and mutational analyses have exposed how this TCR recognizes CD1d/glycolipid complexes. First, the crystal structure of a human iNKT TCR in complex with

Cognate recognition and activation of iNKT cells by foreign antigen

Microbial glycolipids presented as cognate antigens that activate iNKT cells have been identified. iNKT cells have been shown to directly recognize α-linked glycosphingolipids and diacylglycerol antigens that are expressed by bacteria such as Sphingomonas, Ehrlichia and Borrelia burgdorferi in a CD1d-dependent manner [49, 63, 64, 65] (Figure 1C). The biological response to these glycolipid antigens includes the production of IFNγ and IL-4 by iNKT cells. Because these bacteria lack

The ‘Swiss-Army knife’ of the immune system: how can iNKT cells do so many things?

It is becoming increasingly clear that iNKT cells can and do respond differently under different circumstances. Yet how do iNKT cells achieve this? Do iNKT cells represent a single population of cells with the plasticity to perform multiple tasks depending upon environmental cues? Or, do iNKT cells comprise a collection of many distinct subpopulations, each with unique functional attributes? Owing to space limitations we will not detail the putative roles of iNKT cells in the numerous disease

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to colleagues whose works were not cited owing to space constraints or omission. This work was supported by National Institutes of Health Grant (AI057485).

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