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The unique role of natural killer T cells in the response to microorganisms

Nature Reviews Microbiology volume 5, pages 405–417 (2007)Cite this article

Key Points

  • Natural killer T (NKT) cells are lymphocytes that express both a T-cell receptor (TCR), characteristic of adaptive immunity, and surface receptors for NK cells, which are part of the innate immune response. These cells influence diverse immune responses, including the surveillance for tumours, the maintenance of self-tolerance and the regulation of autoimmune diseases.

  • A major population of NKT cells, called iNKT cells, expresses an invariant TCR α-chain. In mice, this chain is encoded by Vα14 (Vα14i), whereas in humans it is encoded by the orthologous Vα24 gene segment (Vα24i). In contrast to conventional T cells that recognize peptides presented by the major histocompatibility complex (MHC), iNKT cells recognize lipids presented by CD1d molecules.

  • iNKT cells have been shown to have protective roles in host defence against various microbial pathogens, including bacteria, fungi, parasites and viruses. However, these cells are detrimental to the host in a few cases.

  • iNKT cells can be activated in the absence of microbial antigens in several ways. First, endogenous ligand(s) presented by CD1d can mediate TCR stimulation. Second, inflammatory cytokines such as interleukin (IL)-12 and IL-18 produced by antigen-presenting cells (APCs) that have been stimulated by Toll-like receptor (TLR) agonists can activate iNKT cells. Finally, endogenous ligands can combine with the inflammatory cytokines.

  • Recently it has been shown that iNKT cells can be directly activated when their invariant TCR is engaged by glycosphingolipids or glycosyl-diacylglycerols from Sphingomonas spp. or Borrelia burgdorferi, respectively. In these cases, TLR-mediated activation of APCs is not required.

  • These different activation pathways allow iNKT cells to respond to many infectious agents, and render these cells capable of contributing to the host defence against these pathogens.

Abstract

Natural killer T (NKT) cells combine features of the innate and adaptive immune systems. Recently, it has become evident that these T cells have crucial roles in the response to infectious agents. The antigen receptor expressed by NKT cells directly recognizes unusual glycolipids that are part of the membrane of certain Gram-negative bacteria and spirochetes. Moreover, even in the absence of microbial glycolipid antigens, these T cells respond to innate cytokines produced by dendritic cells that have been activated by microbes. This indirect sensing of infection, by responding to cytokines from activated dendritic cells, allows NKT cells to react to a broad range of infectious agents.

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Figure 1: Antigen recognition by T cells.
Figure 2: Structure of a glycolipid bound to, or presented by, CD1d.
Figure 3: Structure of some microbial glycolipid antigens recognized by iNKT cells.
Figure 4: Invariant natural killer T (iNKT) cells have different pathways leading to their activation.

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Acknowledgements

We thank our colleagues for many helpful discussions and D. Wu and D. Zajonc for help with preparation of the figures. This work was supported by National Institutes of Health grants (M.K.) and a grant from the Cancer Research Institute (Y.K.).

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Author notes

  1. Emmanuel Tupin and Yuki Kinjo: These authors contributed equally to this work.

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  1. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, 92037, California, USA

    Emmanuel Tupin, Yuki Kinjo & Mitchell Kronenberg

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Correspondence to Mitchell Kronenberg.

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DATABASES

Entrez Genome Project

Borrelia burgdorferi

Chlamydia trachomatis

Escherichia coli

Leishmania major

Listeria monocytogenes

Mycobacterium tuberculosis

Pseudomonas aeruginosa

Salmonella typhimurium

Schistosoma mansoni

Streptococcus pneumoniae

Toxoplasma gondii

FURTHER INFORMATION

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Glossary

Lyme disease

Named after Lyme, Connecticut, USA, where it was described, this disease is found in North America and Europe in some individuals bitten by Ioxedes ticks (deer ticks). It consists of a rash and flu-like symptoms in its initial stages, followed by musculoskeletal, arthritic, neurological, psychiatric and/or cardiac manifestations in individuals not treated early on with antibiotics.

Toll-like receptor

(TLR). TLRs constitute a family of receptors of the innate immune system. Different members are found on the plasma membrane or on intracellular membranes. These molecules have leucine-rich repeats and they signal through adaptor proteins such as myeloid differentiation primary-response gene 88 (MyD88) to activate production of interleukin (IL)-12 and other cytokines. They are pattern-recognition receptors, meaning that they recognize certain molecules such as peptidoglycans, lipopolysaccharides or double-stranded RNA molecules that are broadly shared by many microorganisms.

Glycocalyx

The general term referring to an extracellular network of polysaccharides that project from the cellular surfaces of some bacteria, epithelia and other cells.

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Tupin, E., Kinjo, Y. & Kronenberg, M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5, 405–417 (2007). https://doi.org/10.1038/nrmicro1657

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