Key Points
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Whereas peptide–MHC complexes are the usual model for technology development focused on T cells, the discovery of lipids and non-lipid small molecules presented by CD1 and MHC class I-related protein (MR1) proteins expands the range of physiological antigens for human T cell responses.
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The human CD1 system consists of four antigen-presenting molecules, each with a different cell biological function. Most prior work on this system has focused on CD1d recognition by natural killer T (NKT) cells, but newly developed tetramers comprised of human CD1a, CD1b or CD1c molecules have created an opportunity to measure T cell function ex vivo in disease states.
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Many bacteria and fungi produce vitamin B metabolites (modified ribityl lumazines and ribityl pyrimidines), some of which can covalently bind in the A′ pocket of MR1 molecules and activate mucosal-associated invariant T (MAIT) cells.
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Whereas antigen-presenting cells trim large proteins into peptide antigens to fit the MHC groove, CD1 antigen processing starts with lipids that mostly match the CD1 cleft volume. Lipid antigens that are smaller than the cleft bind concomitantly with spacer lipids, and larger lipids are thought to protrude from the interior of CD1 proteins through accessory portals.
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Peptides span broadly across both sides of the MHC antigen display platform. Lipids bound to CD1 enter the T cell receptor (TCR) contact platform from the right side. This mode of binding creates a situation in which TCRs can predominantly contact CD1 protein or lipid, depending on whether the TCR takes a right-sided or left-sided approach.
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An unexpected mechanism for T cell autoreactivity was recently discovered in which a TCR binds directly to CD1a rather than to lipids carried in the cleft.
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Cellular CD1a proteins bind certain lipids with large head groups that disrupt the surface of CD1a. Such non-permissive ligands act by interfering with TCR contact to CD1a.
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NKT cells and MAIT cells are defined by TCRs that are nearly identical in all humans, and they bind CD1d and MR1 antigen-presenting molecules that are also nearly the same in all humans. New studies show that such invariant TCRs exist in the CD1b system and might be common in the human TCR repertoire.
Abstract
The antigen-presenting molecules CD1 and MHC class I-related protein (MR1) display lipids and small molecules to T cells. The antigen display platforms in the four CD1 proteins are laterally asymmetrical, so that the T cell receptor (TCR)-binding surfaces are comprised of roofs and portals, rather than the long grooves seen in the MHC antigen-presenting molecules. TCRs can bind CD1 proteins with left-sided or right-sided footprints, creating unexpected modes of antigen recognition. The use of tetramers of human CD1a, CD1b, CD1c or MR1 proteins now allows detailed analysis of the human T cell repertoire, which has revealed new invariant TCRs that bind CD1b molecules and are different from those that define natural killer T cells and mucosal-associated invariant T cells.
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Acknowledgements
The authors thank R. Birkinshaw, J. Le Nours, S. Huang, T.-Y. Cheng and K. Wucherpfennig for advice and graphical images. This work is supported by the Bill and Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases (NIAID; grants AI049313, AI111224 and U19 111224), National Health and Medical Research Council (NHMRC) of Australia (1013667 and 1083942), Australian Research Council (DP140100977 and CE140100011), Cancer Council of Victoria (1042866), NHMRC Senior Principal Research Fellowship (to D.I.G.; 1020770) and NHMRC Australia Fellowship (to J.R.; AF50). All figures, including figure 1 and figure 5b, are original.
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Glossary
- Accessory portals
-
Small gaps present in the side or bottom of the clefts present in CD1b (C′ portal) and CD1c (D′ and E′ portals). Whereas the main F′ portal is present in all CD1 proteins and allows antigen contact with T cell receptors (TCRs), accessory portals probably have a separate sizing function that allows lipids to partially escape from the interior of the cleft at a site distant from TCR contact.
- Tetramers
-
Reagents comprised of a fluorophore-conjugated core surrounded by four antigen-presenting molecules (for example, MHC class l, CD1 or MR1). Antigen-loaded tetramers bind antigen-specific T cell receptors with sufficient avidity so that antigen-specific T cells can be directly counted or isolated by flow cytometry.
- Wax esters
-
Fatty acids linked to an alcohol to form hydrophobic lipids, including those that accumulate on the skin surface.
- Squalene
-
An abundant, organ-specific polyunsaturated branched chain lipid with 30 carbons that accumulates in the skin and activates T cells via CD1a.
- Scaffold lipids
-
Specialized types of spacer lipid that are located within the lower section (T′ tunnel) of the CD1b cleft. Scaffold is an analogy to building scaffolds, which provide upwards-directed support to larger objects, which in this case is the antigen.
- Class II-associated invariant chain peptide
-
(CLIP). A short amino acid sequence in the invariant chain that binds within the MHC class II groove shortly after translation so that it functions to block loading of self peptides during the early stages of MHC class II exit from the endoplasmic reticulum and Golgi apparatus.
- Secretory pathway
-
A series of protein transport reactions in which newly folded proteins transit from the endoplasmic reticulum to the Golgi apparatus and to the cell surface. For CD1, this pathway provides self lipids that are loaded onto CD1 proteins at neutral pH.
- Endosomal recycling
-
A process by which CD1 proteins shuttle from the cell surface to the endosomal network and back. CD1b, CD1c and CD1d proteins contain tyrosine-containing motifs in their cytoplasmic tails that mediate binding to adaptor proteins and transport to endosomes and lysosomes, where lipids derived from outside the antigen-presenting cell bind CD1 proteins at neutral or acidic pH.
- Spacer lipids
-
Hydrophobic compounds that bind alongside antigenic lipids and fill up part of the CD1 cleft that is not occupied.
- Mucosal-associated invariant T cells
-
(MAIT cells). T cells that express a structurally conserved invariant T cell receptor and are selected by MR1.
- Sebum
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Mixed hydrophobic oils that are produced by glands in the hair follicles and released to form an outer protective barrier on the skin surface.
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Van Rhijn, I., Godfrey, D., Rossjohn, J. et al. Lipid and small-molecule display by CD1 and MR1. Nat Rev Immunol 15, 643–654 (2015). https://doi.org/10.1038/nri3889
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DOI: https://doi.org/10.1038/nri3889
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