CD1d‐Restricted Natural Killer T Cells

Abstract

Natural killer T (NKT) cells that express the semi‐invariant T‐cell receptor are innate‐like lymphocytes whose functions are controlled by self and foreign glycolipid ligands. Such ligands are presented by the antigen‐presenting, MHC class I‐like molecule CD1d, which belongs to a family of lipid antigen‐presenting molecules collectively called CD1. Activation of NKT cells results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self‐antigens. The nature of CD1d‐restricted ligands, the manners in which they are recognised and the unique effector functions of NKT cells suggest an immunoregulatory role for this T‐cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine responses to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This article summarises our current understanding of CD1d‐restricted NKT cell biology and how these innate‐like lymphocytes control inflammation.

Key Concepts

  • CD1d molecules belong to a family of lipid antigen‐presenting molecules collectively called CD1.
  • CD1d molecules resemble peptide antigen‐presenting MHC class I molecules.
  • CD1d molecules restrict the specificity and functions of Natural killer T (NKT) cells.
  • NKT cells recognise self‐ and nonself‐lipid ligands.
  • Antigen recognition quickly activates NKT cells, which respond immediately by releasing proinflammatory and immunoregulatory cytokines and chemokines.
  • Activated NKT cells communicate with cells of the innate and adaptive immune systems by cell–cell interactions and/or via soluble mediators.
  • Such communications allow NKT cells to control immune responses to microbial pathogens and certain cancers.
  • NKT‐cell activation has beneficial and, sometimes, adverse effects on certain autoimmune and metabolic disorders.
  • NKT cells are targets for vaccine adjuvants and immunotherapies.

Keywords: CD1d molecules; NKT cells; glycolipid‐reactive T cells; innate‐like T cells; glycosphingolipids; α‐galactosylceramide; immunoregulation

Figure 1. Three distinct strategies activate NKT cells. Potent NKT‐cell agonists – such as αGalCer – directly activate NKT cells without the need for a second signal in a TCR‐signalling dominated manner (a). Alternatively, microbes containing TLR ligands such as LPS activate NKT cells by inducing IL‐12 production by DC, which amplifies weak responses elicited upon the recognition of CD1d bound with self‐glycolipids by the NKTCR. Several endogenous lipid agonists have been identified and characterised (Table). Some microbes such as , which are α‐Proteobacteria, synthesise α‐anomeric glycolipids for their cell walls. These glycolipids, when presented by CD1d, weakly activate NKT cells directly. In the presence of a second signal – generally a proinflammatory cytokine such as IL‐12 – it strongly activate NKT cells (b). Intriguingly, NKT cells can be activated solely by cytokines – mainly IL‐12 plus IL‐18 – in a TCR‐independent manner (c).
Figure 2. Topologic biochemistry and the assembly of CD1d with NKT‐cell antigen. (a) CD1d assembly with lipids begins within the rough endoplasmic reticulum (ER) with the assistance of several chaperones. Partially folded α‐chain–β2m complex is then thought to bind ER‐resident lipids with the assistance of lipid‐transfer proteins (LTP) such as microsomal triglyceride transfer protein (MTP), a protein that facilitates the assembly of apolipoprotein B. Upon complete assembly, the CD1d–lipid complexes egress from the ER and negotiate the secretory pathway to the plasma membrane. By virtue of late endosome/lysosome‐targeting motif (tyrosine‐glutamine‐glycine‐valine‐leucine and tyrosine‐glutamine‐aspartate‐isoleucine‐arginine in human and mouse CD1d, respectively) within the cytoplasmic tail of CD1d, it recycles through the MHC class II‐enriched compartment (MIIC). During its time in the MIIC (late endosomes/lysosomes), CD1d exchanges its ER‐loaded lipids for antigenic glycolipids that activate NKT cells . The extraction of bound lipids from CD1d and the loading of antigenic glycolipids are facilitated by lysosomal LTP such as Saposins (Sap), GM2 activator (GM2A) and Niemann–Pick C‐2 (not shown), which are essential for the enzymatic catabolism of glycolipids. (b) Infection of Mφ and DC delivers microbes to the CD1d‐containing lysosomes. Differential interference contract (DIC) picture of Mφ observed under a light microscope showing the gross cellular outline; the prominent structure within this cell is its nucleus. Cellular organelles and their contents are observed by confocal fluorescence microscopy. In the micrographs shown, the lysosome is stained red because it is marked with a fluorescent dye, Lyso‐tracker; the microbe, in this case , stained with the fluorescent dye PKH‐II, is seen green; CD1d, which is detected with a specific monoclonal antibody 1B1 tagged with the fluorescent dye allophycocyanin, is stained blue. Where colocalises with lysosomes and CD1d colocalised appear white in the merged picture.
Figure 3. The structures of CD1d‐restricted glycolipid antigens. (a) Lateral view of the three‐dimensional structure of mouse CD1d bound to the potent agonist αGalCer. The CD1d molecule is made up of a heavy chain that is noncovalently associated with a light‐chain β2‐microglobulin (β2m). The membrane distal α1 and α2 domains of the heavy chain fold in such a manner that they form an apical antigen‐binding groove into which bind lipid ligands. The α3 domain, which adopts an immunoglobulin constant domain‐like fold, is intermediary between the antigen‐binding domain and the transmembrane domain that anchors the heterodimer into the plasma membrane. (b) Apical view of the antigen‐binding domain shows the solvent‐exposed sugar of αGalCer. The antigen‐binding groove contains two deep pockets – A′ and F′ – which bind the hydrocarbon tails of the ‐acyl chain and the phytosphingosine base, respectively. (c, d) Close‐up three‐dimensional view of mouse CD1d–αGalCer structure reveals critical amino acid side chains within hydrogen‐bonding distance from atoms of the glycolipid antigen. Mouse (Mo) and human (Hu) sequences are shown for comparison, with arrows indicating hydrogen bonds. The three‐dimensional structures were generated with Chimaera (a and c) or PyMol (b) software using published X‐ray crystallographic coordinates (1Z5L, and 2AKR) deposited with the Protein Data Bank.
Figure 4. The immunological effector functions of NKT cells. The interactions between the invariant natural killer (NKT) cell receptor and its cognate antigen and interactions between costimulatory molecules CD28 and CD40 and their cognate ligands CD80/86 (B7.1/7.2) and CD40L, respectively, activate NKT cells. Activated NKT cells participate in cross‐talk between members of the innate and the adaptive immune system by deploying cytokine/chemokine messengers. Upon activation , NKT cells rapidly secrete a variety of cytokines/chemokines. These cytokines/chemokines influence the polarisation of CD4+ T cells towards T helper (Th)1 or Th2 cells as well as the differentiation of precursor CD8+ T cells to effector lymphocytes and B cells to antibody‐secreting plasma cells. Some of these cytokines/chemokines facilitate the recruitment, activation and differentiation of macrophages and dendritic cells, which result in the production of interleukin (IL)‐12 and possibly other factors. IL‐12, in turn, stimulates NK cells to secrete IFN‐γ. Thus, activated NKT cells have the potential to enhance as well as temper the immune response. This schematic rendition of NKT‐cell effector functions is an adaptation of past reviews (Brennan ., ; Florence ., ; Van Kaer, ).
Figure 5. A putative NKT‐cell ontogenetic pathway. Early steps (dashed arrow), CD4 and CD8 double‐negative through immature CD8 single‐positive stages (not shown) that precede the CD4 and CD8 double‐positive (DP) stage of thymocyte development are common to both NKT lymphocyte and conventional T‐cell lineages. The ontogenetic programming of the unique features of NKT‐cell function occurs at the DP stage; it begins with the rearrangement of the to TCR α‐chain gene segments and after its interaction with the positively selecting ligand, CD1d/self‐lipid complex. Stage‐specific NKT‐cell markers – for example, CD24 (heat‐stable antigen), CD44 and NK1.1 (CD161) – and lineage‐specific differentiation signals are indicated. IL‐7 and IL‐15 are cytokines that utilise specific (IL‐7Rα and IL‐15Rα, respectively) and the shared common γ chain (γc) receptor protein subunits that mediate intercellular communication. IL‐15 also uses IL‐2Rβ that it shares with IL‐2 for intercellular communication. CD1d and pre‐T‐cell receptor (TCR)‐α (pre‐Tα) are structural proteins, while segment and Cβ FG‐loop are structural parts of the TCR essential for positive selection of NKT cells. TCR signalling turns on the master transcription factor PLZF, which controls multiple molecular events that distinguish NKT cells from all of the other thymus‐derived lymphocytes. Fyn and Lck are Src (cellular protein homologous to the oncogene) kinases (protein phosphorylation enzymes) essential for transmitting TCR signals from the plasma membrane to inside of the cell. Fyn also transmits signals relayed from SLAM (signalling lymphocyte activation molecule) through the adapter protein SAP (SLAM‐associated protein). Protein kinase C (PKC)‐θ processes TCR signalling and activates nuclear factor‐κB (NF‐κB), which is a transcription factor. Other transcription factors such as Egr‐2, Ets‐1, GATA3, Id2, Id3, MEF, Nur77, RORγt and T‐bet, some of which are also essential for functional differentiation of NKT‐cell subsets (see Figure), are also depicted.
Figure 6. Four NKT‐cell subsets and the division of labour. The four currently defined NKT‐cell subsets are operationally defined and shadow the conventional Th1, Th2, Th17 and Treg subsets. The expression of subset‐specific transcription factors and the secretion of subset‐specific prototypic effector molecules define the four NKT‐cell subsets. The reported location of the subsets and their functions are also shown. The text contains detailed description of each subset.
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Further Reading

Bendelac A, Savage PB and Teyton L (2007) The biology of NKT cells. Annual Review of Immunology 25: 297–336.

Brennan PJ, Brigl M and Brenner MB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nature Reviews Immunology 13: 101–117.

Godfrey DI and Berzins SP (2007) Control points in NKT‐cell development. Nature Reviews Immunology 7: 505–518.

Kotas ME and Medzhitov R (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160: 816–827.

Macho‐Fernandez E and Brigl M (2015) The extended family of CD1d‐restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions. Frontiers in Immunology 6: 362.

Rossjohn J, Gras S, Miles JJ, et al. (2015) T cell antigen receptor recognition of antigen‐presenting molecules. Annual Review of Immunology 33: 169–200.

Terabe M and Berzofsky JA (2014) The immunoregulatory role of type I and type II NKT cells in cancer and other diseases. Cancer Immunology, Immunotherapy 63: 199–213.

Van Kaer L, Parekh VV and Wu L (2011) Invariant NK T cells: potential for immunotherapeutic targeting with glycolipid antigens. Immunotherapy 3: 59–75.

Van Kaer L, Parekh VV and Wu L (2013) Invariant natural killer T cells as sensors and managers of inflammation. Trends in Immunology 34: 50–58.

Wu L and Van Kaer L (2013) Contribution of lipid‐reactive natural killer T cells to obesity‐associated inflammation and insulin resistance. Adipocyte 2: 12–16.

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Hill, Timothy M, Bezbradica, Jelena S, Van Kaer, Luc, and Joyce, Sebastian(Jan 2016) CD1d‐Restricted Natural Killer T Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020180.pub2]