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  • Review Article
  • Published:

The unconventional lifestyle of NKT cells

Nature Reviews Immunology volume 2, pages 557–568 (2002)Cite this article

Key Points

  • Vα14i T cells are the main natural killer T (NKT)-cell subset in mice, and a homologous Vα24i T-cell population is present in humans.

  • Vα14i T cells have an invariant T-cell receptor (TCR) α-chain, although the complementarity-determining region 3 (CDR3) of their β-chain is not selected; they have some degree of autoreactivity for CD1d; and they have a memory phenotype.

  • Vα14i T cells almost uniformly recognize the synthetic glycolipid α-galactosyl ceramide (α-GalCer) presented by CD1d. This causes the release of cytokines, which can influence various types of immune cell, including dendritic cells, macrophages and lymphocytes.

  • The ability of Vα14i T cells to rapidly produce quantities of interleukin-4 (IL-4) that can be detected systemically after in vivo stimulation distinguishes them from other lymphocyte populations.

  • Vα14i T cells have unique genetic and cellular requirements for their development in the thymus, including selection by bone-marrow-derived, rather than epithelial, cells. Despite their distinct properties, similar to other T cells, Vα14i T cells originate from a double-positive intermediate.

  • The Vα14i precursor population expands and is instructed to branch off from the mainstream pathway for thymocyte development, with the acquisition of NK1.1 expression being a late maturation event. The factor that is responsible for this branching off is unknown, but unique features of the TCR interaction or selection by bone-marrow-derived cells could be responsible.

  • Vα14i T cells produce large quantities of cytokines rapidly after activation, and then probably undergo activation-induced cell death, without evidence of clonal expansion.

  • Vα14i T cells influence various immune responses, including tumour rejection, the maintenance of self-tolerance, autoimmunity and the response to several infectious agents. In some cases, this requires stimulation with α-GalCer, but a natural role for Vα14i T cells in model systems has been elucidated also.

  • There is no final common pathway for the effects of Vα14i T-cell stimulation. In some instances, the production of IL-4 and/or IL-10 might be crucial, but in others, interferon-γ is most important.

Abstract

Many characteristics distinguish CD1d-reactive natural killer T (NKT) cells that express the invariant Vα14–Jα18 T-cell receptor (known here as Vα14i T cells) from conventional T cells. Because of their apparent self-reactivity, their expression of natural-killer receptors and their capacity to secrete large quantities of cytokines rapidly — including interferon-γ and interleukin-4 — it has been proposed that Vα14i T cells might be important for the initiation and regulation of immune responses. New studies are beginning to shed light on the development, selection, homeostasis and possible function(s) of Vα14i T cells, which are 'non-conformists' compared with the main T-cell populations. These studies might lead to the development of techniques for the controlled manipulation of the Vα14i T-cell response, which could one day form the basis of immune therapies.

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Figure 1: Aberrant TCR expression in NKT TCR-transgenic mice.
Figure 2: Schematic view of the development of Vα14i T cells in the thymus.
Figure 3: A model for the avidity-based, instructional selection of Vα14i T cells.

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Acknowledgements

We thank our many colleagues for helpful discussions and sharing of unpublished data; space limitations prevented the citation of many relevant references. M.K. is supported by grants from the National Institutes of Health. L.G. is the recipient of a fellowship from the Cancer Research Institute. This is publication number 474 from the La Jolla Institute for Allergy and Immunology.

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Authors and Affiliations

  1. La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, California, USA

    Mitchell Kronenberg & Laurent Gapin

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  1. Mitchell Kronenberg
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Correspondence to Mitchell Kronenberg.

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DATABASES

LocusLink

β-actin

CD1B

CD1C

CD1D

CD1d

CD2

CD3ɛ

CD8

CD49B

CD95

CD95L

CD161

Ets1

Fyn

γc

IFN-γ

IL-2

IL-4

IL-7

IL-10

IL-12

IL-13

IL-15

LFA1

LT

LTβ receptor

MCP1

Mek

NK1.1

TNF

TRAIL

Zap70

FURTHER INFORMATION

CD1 and NKT Cell Workshop 2002

KIRIN Pharmaceutical Research Corporation

Mitchell Kronenberg

Glossary

α-GALCER–CD1D TETRAMER

A complex of four CD1d molecules loaded with α-GalCer that has sufficient affinity to detect the cell-surface Vα14i T-cell receptor by flow cytometry.

FETAL THYMIC ORGAN CULTURE

Removal of day-16 fetal thymi allows the analysis of antigen-driven positive- and negative-selection events during in vitro culture.

NU/NU MICE

nu/nu or nude mice have a spontaneous mutation that leads to hairlessness and epithelial defects, including the loss of a functional thymus.

HANGING-DROP CULTURE

A method for analysing lymphocyte development in vitro by seeding thymic lobes with defined precursor populations. Lymphoid thymic remnants and precursor populations are added together in a small volume of liquid in a Terasaki plate, and the plate is immediately inverted to form a 'hanging drop'. The hanging drop allows the precursor cells to enter into and seed the thymic lobe.

RAG

Recombination-activating gene. Rag1 and Rag2 are closely linked genes that constitute the catalytic machinery for gene-segment recombination of antigen-receptor genes.

CD4+CD25+ REGULATORY T CELLS

Naturally occurring T cells that have potent regulatory activity, including the ability to inhibit autoimmune diabetes in mice, induce tolerance to alloantigens, impede anti-tumour immunity and regulate the expansion of other peripheral CD4+ T-cell populations.

MYELOID DENDRITIC CELLS

A subset of CD8α− dendritic cells that might be important for initiating vigorous immune responses.

T HELPER 1/T HELPER 2

(TH1/TH2). There are two patterns of cytokine production that have been described for CD4+ T cells. The TH1 pattern includes pro-inflammatory cytokines (typified by IFN-γ), whereas the TH2 pattern includes cytokines such as IL-4, IL-5 and IL-13.

NOD MICE

Non-obese diabetic (NOD) mice are a strain of mice that spontaneously develop type I diabetes.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

(EAE). Refers to a set of related animal models for multiple sclerosis. Typically, disease is induced by the injection of components of myelin, which leads to demyelination in the central nervous system.

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Kronenberg, M., Gapin, L. The unconventional lifestyle of NKT cells. Nat Rev Immunol 2, 557–568 (2002). https://doi.org/10.1038/nri854

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