Journal Article

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

Brenner, Michael B., Brigl, Manfred, Brennan, Patrick J.

2013

Overview

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. Invariant natural killer T (iNKT) cells are innate-like lymphocytes that express T cell receptors that can be activated by lipid antigens presented on CD1d molecules. Here, the authors describe different models of iNKT cell activation and discuss how activated iNKT cells can contribute to both protective and pathological immune responses. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1619/554/383 / 631/250/262 / 631/250/516 / Animals / Antigen receptors, T cell / Antigens / Biomedical and Life Sciences / Biomedicine / CD1d antigen / Cell activation / Cell Communication - immunology / Cells / Cytokines / Genetic aspects / Health aspects / Humans / Immunity, Innate / Immunology / Inflammation / Killer cells / Leukocytes - immunology / Leukocytes - metabolism / Lipids / Lymphocyte Activation - immunology / Lymphocytes T / Natural immunity / Natural killer cells / Natural Killer T-Cells - immunology / Natural Killer T-Cells - metabolism / Physiological aspects / Receptors / review-article / Self / T cells / T-cell receptor / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / Thymus gland