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  • Review Article
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Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions

Nature Reviews Immunology volume 13, pages 101–117 (2013)Cite this article

Subjects

Key Points

  • Invariant natural killer T (iNKT) cells are a specialized T cell population that recognizes lipid antigens that are presented by a cell-surface molecule known as CD1d. They have been shown to have important roles in many diverse immune responses.

  • iNKT cells recognize both foreign lipid antigens and self lipid antigens. The T cell receptor (TCR)–lipid–CD1d interaction is similar for both self and foreign lipid antigens, despite the differences that exist in these lipid structures. Strong lipid antigens have a 'lock and key' type of binding, whereas weaker antigens require an 'induced fit' mechanism.

  • The production of lipid self antigens for iNKT cells can be upregulated by antigen-presenting cells (APCs) in response to danger signals, such as Toll-like receptor (TLR) agonists. This provides a mechanism for iNKT cell activation in the absence of foreign lipid antigens.

  • In addition to being activated through their TCRs in response to CD1d-presented lipids, iNKT cells can be activated by indirect stimuli, such as pro-inflammatory cytokines. During many infections, interleukin-12 (IL-12) may have an equally important role to lipid antigens in activating iNKT cells.

  • iNKT cells couple the rapid activation kinetics of innate immune cells with the diverse effector functions of adaptive T cells. Early activation during infection leads to rapid cytokine production in target tissues by polarized iNKT cell subsets.

  • Interactions between iNKT cells and CD1d-expressing APCs lead to bidirectional activation. Cytokines produced by iNKT cells activate and recruit other cell types early during immune responses, while activated APCs direct the ensuing adaptive immune responses. Thus, iNKT cells and their lipid antigens help to orchestrate innate and adaptive immune responses.

Abstract

Invariant natural killer T (iNKT) cells exist in a 'poised effector' state, which enables them to rapidly produce cytokines following activation. Using a nearly monospecific T cell receptor, they recognize self and foreign lipid antigens presented by CD1d in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses. In this Review, we discuss recent advances in our understanding of the innate-like mechanisms underlying iNKT cell activation and describe how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iNKT cells in health and disease.

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Figure 1: Selected iNKT cell lipid antigens and closely related non-antigenic lipids.
Figure 2: The mode of binding for an iNKT cell TCR.
Figure 3: TCR- and cytokine-driven activation of iNKT cells.
Figure 4: iNKT cell subsets.
Figure 5: Interactions between iNKT cells and other leukocytes.
Figure 6: iNKT cells during microbial infection.

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Acknowledgements

P.J.B. is supported by a career development award from the American Academy of Allergy, Asthma and Immunology ARTrust. M.B. is supported by the US National Institutes of Health (grant AI077795). M.B.B. is supported by research grants from the US National Institutes of Health (AI063428, AI028973 and DK057521) and the American Diabetes Association (7-12-IN-07). We thank R. Tatituri, E. Kim and L. Lynch for helpful discussions during the preparation of this manuscript. We also thank J. Rossjohn for providing the protein crystal structures shown in Fig. 2.

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  1. Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, One Jimmy Fund Way, Boston, 02115, Massachusetts, USA

    Patrick J. Brennan & Michael B. Brenner

  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Manfred Brigl

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Glossary

Somatic recombination

(Also known as V(D)J recombination). The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T cell and B cell receptors.

Omentum

The folds of peritoneum between the stomach and abdomen that contain lymphoid aggregates known as 'milky spots'.

Sickle cell disease

An inherited disorder of erythrocytes, with a high prevalence in African and African American populations, that is caused by a mutation in the β-globin gene. A single nucleotide substitution (and the resultant amino-acid substitution) leads to the polymerization of haemoglobin when it is deoxygenated, ultimately resulting in the occlusion of small blood vessels. Disease manifestations include chronic anaemia, multiple painful crises, organ damage and increased susceptibility to bacterial infections.

MicroRNAs

Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

Gangliosides

A group of glycosphingolipids that are prominent components of nerve cell membranes.

β2-microglobulin

A protein comprising a single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2-microglobulin, MHC class I molecules are unstable and are therefore found at very low levels on the cell surface.

Complementarity-determining region 3

(CDR3). The CDRs are the amino-acid sequences of the B cell receptor and the T cell receptor that physically contact the antigen and are the most variable parts of the receptors. There are three such regions — CDR1, CDR2 and CDR3 — in each receptor chain. CDR3 arises from recombination of the variable (V), diversity (D) and joining (J) regions of each receptor chain and is the most variable CDR.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. The restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

NK cell transactivation

The secondary activation of a natural killer (NK) cell by interleukin-12 (IL-12), which leads to the production of interferon-γ. This process occurs following the primary activation of an IL-12- producing cell type, such as an activated dendritic cell.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

M2 macrophages

Macrophages that differentiate in response to interleukin-4 (IL-4) or IL-13 and are thought to mediate T helper 2-type immune responses, such as protection from parasites and wound healing. M2 macrophages are typically defined by their expression of arginase 1, the mannose receptor CD206 and the IL-4 receptor -chain, and they can produce large amounts of IL-10.

Myeloid-derived suppressor cell

(MDSC). A member of a heterogeneous population of immature myeloid cells with immunosuppressive functions. MDSCs can accumulate in tissues during inflammation or in response to tumour-derived cytokines.

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Brennan, P., Brigl, M. & Brenner, M. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13, 101–117 (2013). https://doi.org/10.1038/nri3369

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