NKT cells: T lymphocytes with innate effector functions

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Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens in the context of the MHC class I-related glycoprotein CD1d. Recent studies have identified multiple ways in which NKT cells can become activated during microbial infection. Mechanisms of CD1d-restricted antigen presentation are being unraveled, and a surprising connection has been made to proteins that control lipid metabolism and atherosclerosis. It appears that several microorganisms have developed strategies to interfere with the CD1d antigen-presentation pathway. New studies have also provided important insight into the mechanisms that control effector cell differentiation of NKT cells and have revealed specialized functions of distinct NKT cell subsets. Finally, there is continued enthusiasm for the development of NKT cell-based therapies of human diseases.

Introduction

It is now well established that some T lymphocytes can react with lipid and glycolipid antigens rather than with peptides [1]. This antigen-specificity is characteristic of T lymphocytes that are restricted by the MHC class I-related antigen-presenting molecule CD1d [1]. CD1d-restricted T cells express phenotypic markers that are typical of conventional T cells and natural killer (NK) cells, and these cells are therefore referred to as natural killer T (NKT) cells. Two subtypes of CD1d-restricted NKT cells have been identified [2] (Figure 1). Type I NKT cells, also called invariant NKT (iNKT) cells, have a highly restricted T-cell receptor (TCR) repertoire and express TCR Vα14–Jα18 and Vβ8.2, -7 or -2 chains in mice and homologous TCR Vα24–Jα18 and Vβ11 chains in humans. Type II NKT cells, which are also referred to as non-iNKT cells, express a more diverse TCR repertoire.

Most studies using NKT cells have focused on iNKT cells. All iNKT cells from mice and humans react with the marine sponge-derived glycolipid α-galactosylceramide (α-GalCer; Figure 1a); consequently, staining with fluorescently labeled α-GalCer-loaded CD1d molecules is a reliable way to identify these cells [2]. A hallmark of iNKT cells is their capacity to rapidly (within hours) produce a mixture of T helper type 1 (Th1) and Th2 cytokines upon TCR engagement [1, 3, 4]. Stimulation of iNKT cells in this manner also results in the activation of a variety of other cell types, including dendritic cells (DCs), NK cells, B cells and conventional T cells. Consequently, iNKT cell activation can strongly impact adaptive immune responses and can influence a wide array of host defenses and pathologies. However, the mechanisms of iNKT cell activation and immune modulation remain poorly understood. Because of their potent immunomodulatory properties, iNKT cells hold great promise as targets for the development of vaccine adjuvants and immunotherapies. Preclinical studies have demonstrated that the iNKT cell ligand α-GalCer and related glycolipids exhibit therapeutic activities against several tumors and a variety of autoimmune and inflammatory diseases, but mechanisms have remained poorly understood [1, 3, 4].

In this review, I will highlight progress made during the past two years in understanding the specificity, mechanisms of activation, effector functions and therapeutic properties of iNKT cells and, where available, non-iNKT cells.

Section snippets

Physiological NKT cell antigens

Recent studies have provided much insight into the physiological antigens that can activate NKT cells. Although reactivity of iNKT cells to α-GalCer was demonstrated several years ago, this reagent was derived from a marine sponge and, therefore, has been thought to be a mimic of a natural endogenous or exogenous ligand. Reactivity of iNKT cells with lipids derived from certain autologous cells, tumors, microbes and pollen has been documented [5], but this reactivity appears to be restricted to

CD1d-restricted antigen-presentation mechanisms

Studies over the past several years have provided evidence for remarkable relationships between the CD1d antigen-presentation pathway and lipid metabolism [13, 14] (Figure 2). CD1d molecules are synthesized in the endoplasmic reticulum, where they initially assemble with cellular phosphatidylinositol (PtdIns) and/or PtdIns-glycans, which are thought to stabilize the hydrophobic CD1d-binding pocket and facilitate CD1d transport to the cell surface [15]. A few years ago, it was demonstrated that

Microbial subversion of CD1d-restricted antigen presentation

Because NKT cells play a crucial role in protective immune responses against a variety of microbial pathogens, it is not surprising that pathogens, in particular viruses that establish latency, have devised ways to interfere with the CD1d antigen-presentation pathway. Several elegant mechanisms have been identified [18] (Figure 2). The modulator of immune recognition (MIR) proteins of Kaposi sarcoma-associated herpesvirus promote the downregulation of cell surface CD1d expression [19]. MIR1

Mechanisms of NKT cell activation

CD1d is expressed on a variety of cell types, including CD4+CD8+ thymocytes, hepatocytes, B cells, macrophages and DCs, but the identity of the physiological APCs that are responsible for iNKT cell activation in vivo has remained unclear. Two groups of investigators recently demonstrated that DCs are crucially important for activating iNKT cells in vivo following α-GalCer treatment of mice [26•, 27•]. Presentation of α-GalCer by DCs resulted in profound Th1 and Th2 cytokine production and NK

NKT cell development, effector differentiation and homeostasis

Like conventional T cells, NKT cells develop in the thymus [36]. CD1d is required for positive selection of iNKT cells, which is mediated by double-positive (DP) thymocytes rather than by thymic epithelial cells. As hexb-deficient mice are defective in iNKT cell maturation, it has been suggested that iGb3 functions as an endogenous iNKT cell agonist that mediates positive selection of these cells [6]. However, because mice that carry a diverse range of mutations that affect glycolipid

NKT cell functions

iNKT cells have been implicated in immune responses against infectious agents, tumors and tissue grafts and in regulating a variety of autoimmune and inflammatory diseases [1, 3, 4, 29]. Recent studies have further revealed a role of iNKT cells in regulating hematopoiesis, during both steady-state conditions and conditions of activation (i.e. α-GalCer treatment) [58]. Consequently, iNKT cell-deficient mice displayed impaired hematopoiesis. These effects of iNKT cells correlated with their

Functions of distinct NKT cell subsets and subtypes

Two main populations of iNKT cells have been identified: CD4+ and CD4CD8 (double negative [DN]) iNKT cells. However, functional differences between these distinct subsets of iNKT cells have remained unclear [73]. A recent article compared the antitumor activities of CD4+ and DN iNKT cells from different organs in mice [74]. It was found that the DN subset of iNKT cells in the liver had superior antitumor activities to the CD4+ subset from liver and both the CD4+ and DN subsets from thymus

Exploiting the effector functions of NKT cells for immunotherapy

There has been continued progress in developing iNKT cell-based adjuvants and immunotherapies of cancer, autoimmune and inflammatory diseases [4, 29, 77]. However, preclinical studies have also revealed that the therapeutic efficacy of α-GalCer is influenced by a wide variety of parameters, including the dose, frequency, timing and route of treatment, as well as the genetic background, sex and age of the animals and the particular animal model that is analyzed.

In mice, significant side-effects

Conclusions

NKT cells are now recognized as bridging the innate and adaptive immune systems. Although important progress has been made regarding the specificity and effector functions of these cells, much remains to be learned. Important areas of future research include: the role of iGb3 and other endogenous glycolipids in NKT cell development and function; the specificity and function of distinct lipid-binding proteins in CD1d-restricted antigen presentation; the relevance of the relationship between

Update

Two recent studies [86•, 87•] have called the physiological role of iGb3 as an endogenous iNKT cell selecting ligand into question. These new findings re-open the search for endogenous iNKT cell antigens.

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I apologize to colleagues whose work I did not cite due to space constraints or omission. I thank members of my laboratory and many collaborators, including Drs. Sebastian Joyce, Yasu Koezuka, Mitchell Kronenberg, Amy Major, Fu-Dong Shi, Ram Singh, Derya Unutmaz, and Chyung-Ru Wang for helpful discussions. I also thank Dr. Sebastian Joyce for critical reading of the manuscript. Work in my laboratory has been supported by grants from the National Institutes of Health (HL68744, AI50953 and

References (87)

  • M. Nowak et al.

    Oral nickel tolerance: Fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells

    J Immunol

    (2006)
  • K. Seino et al.

    Functionally distinct NKT cell subsets and subtypes

    J Exp Med

    (2005)
  • M. Brigl et al.

    CD1: antigen presentation and T cell function

    Annu Rev Immunol

    (2004)
  • D.I. Godfrey et al.

    NKT cells: what's in a name?

    Nat Rev Immunol

    (2004)
  • M. Taniguchi et al.

    The regulatory role of Vα14 NKT cells in innate and acquired immune response

    Annu Rev Immunol

    (2003)
  • M. Kronenberg

    Toward an understanding of NKT cell biology: progress and paradoxes

    Annu Rev Immunol

    (2005)
  • R.R. Brutkiewicz

    CD1d ligands: the good, the bad, and the ugly

    J Immunol

    (2006)
  • D. Zhou et al.

    Lysosomal glycosphingolipid recognition by NKT cells

    Science

    (2004)
  • J. Mattner et al.

    Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections

    Nature

    (2005)
  • Y. Kinjo et al.

    Recognition of bacterial glycosphingolipids by natural killer T cells

    Nature

    (2005)
  • V. Sriram et al.

    Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligand for NKT cells

    Eur J Immunol

    (2005)
  • Y. Kinjo et al.

    Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria

    Nat Immunol

    (2006)
  • A. Jahng et al.

    Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide

    J Exp Med

    (2004)
  • I. Van Rhijn et al.

    CD1d-restricted T cell activation by nonlipidic small molecules

    Proc Natl Acad Sci USA

    (2004)
  • A.S. Major et al.

    Lipid metabolism, atherogenesis and CD1-restricted antigen presentation

    Trends Mol Med

    (2006)
  • G. De Libero et al.

    Mechanisms of lipid-antigen generation and presentation to T cells

    Trends Immunol

    (2006)
  • S. Joyce et al.

    CD1-restricted antigen presentation: an oily matter

    Curr Opin Immunol

    (2003)
  • S.K. Dougan et al.

    Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells

    J Exp Med

    (2005)
  • S. Cho et al.

    Impaired cell surface expression of human CD1d by the formation of an HIV-1 Nef/CD1d complex

    Virology

    (2005)
  • N. Chen et al.

    HIV-1 down-regulates the expression of CD1d via Nef

    Eur J Immunol

    (2006)
  • W. Yuan et al.

    Herpes simplex virus evades NKT cell recognition by suppressing CD1d recycling

    Nat Immunol

    (2006)
  • M.J. Raftery et al.

    CD1 antigen presentation by human dendritic cells as a target for herpes simplex virus immune evasion

    J Immunol

    (2006)
  • C. Roura-Mir et al.

    Mycobacterium tuberculosis regulates CD1 antigen presentation pathways through TLR-2

    J Immunol

    (2005)
  • G.J. Renukaradhya et al.

    Virus-induced inhibition of CD1d1-mediated antigen presentation: reciprocal regulation by p38 and ERK

    J Immunol

    (2005)
  • J. Schmieg et al.

    Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion

    Proc Natl Acad Sci USA

    (2005)
  • D.I. Godfrey et al.

    Going both ways: immune regulation via CD1d-dependent NKT cells

    J Clin Invest

    (2004)
  • L. Van Kaer

    Regulation of immune responses by CD1d-restricted natural killer T cells

    Immunol Res

    (2004)
  • M. Brigl et al.

    Mechanism of CD1d-restricted natural killer T cell activation during microbial infection

    Nat Immunol

    (2003)
  • L. Van Kaer et al.

    Innate immunity: NKT cells in the spotlight

    Curr Biol

    (2005)
  • D.B. Moody

    TLR gateways to CD1 function

    Nat Immunol

    (2006)
  • N.A. Nagarajan et al.

    Invariant natural killer T cells amplify the innate immune response to LPS

    J Immunol

    (2007)
  • T. Mallevaey et al.

    Activation of invariant NKT cells by the helminth parasite Schistosoma mansoni

    J Immunol

    (2006)
  • I. Szatmari et al.

    PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells

    J Exp Med

    (2006)
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