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CD1 antigen presentation: how it works

Key Points

  • CD1 molecules present foreign and self lipids to diverse T cells and natural killer T (NKT) cells. Whereas the clonally restricted diverse T cells mediate adaptive immunity to microbial lipid antigens, the invariant subset of NKT cells mediates innate immune responses, responding rapidly and en masse.

  • The classes of lipids presented by CD1 molecules range from self lipids, such as phospholipids and gangliosides, to microbial lipids, such as mycolic acids, polyketides, ceramides, lipopeptides, sulpholipids and diacylglycerols.

  • CD1 molecules can bind endogenous lipids in the endoplasmic reticulum, where they are assembled. They then follow the secretory pathway to the plasma membrane, before they are internalized. Once internalized, CD1 molecules survey different compartments of the endocytic pathway, load exogenous or different endogenous antigens in these compartments and then return to the plasma membrane for recognition by T cells.

  • Saposins are involved the lysosomal degradation of glycosphingolipids by glycosidic enzymes. Interestingly, this family of proteins has also recently been shown to be involved in the loading of lipid antigens into CD1 molecules.

  • CD1-restricted T cells can be activated by the presentation of cognate microbial antigens or by an indirect mechanism that involves Toll-like receptor stimulation and secretion of interleukin-12, which amplifies the weak CD1-restricted self-lipid reactivity and ensures a rapid activation of a large pool of NKT cells.

Abstract

The classic concept of self–non-self discrimination by the immune system focused on the recognition of fragments from proteins presented by classical MHC molecules. However, the discovery of MHC-class-I-like CD1 antigen-presentation molecules now explains how the immune system also recognizes the abundant and diverse universe of lipid-containing antigens. The CD1 molecules bind and present amphipathic lipid antigens for recognition by T-cell receptors. Here, we outline the recent advances in our understanding of how the processes of CD1 assembly, trafficking, lipid-antigen binding and T-cell activation are achieved and the new insights into how lipid antigens differentially elicit CD1-restricted innate and adaptive T-cell responses.

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Figure 1: Crystal structures of CD1b and mouse CD1d loaded with lipids.
Figure 2: Intracellular trafficking of CD1 molecules.
Figure 3: Lipid loading and exchange in the endocytic pathway.
Figure 4: Strategies for activation mechanisms of CD1-restricted T cells.

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Acknowledgements

We thank R. Grenha and R. Tatituri for valuable help in the preparation of the original figures, M. Brigl, L. Léon, R. Tatituri and D. B. Moody for critical reading of the manuscript and members of our laboratory for helpful discussions. D.C.B. is the recipient of a postdoctoral fellowship from the Arthritis Foundation and M.B.B. is supported by grants of the National Institutes of Health, USA. We apologize to those whose work could not be included due to space limitations.

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Glossary

Endocytic pathway

A trafficking pathway used by all cells for the internalization of molecules from the plasma membrane to lysosomes.

Capping motifs

Carbohydrates that are attached to the branches of the arabinan domain in lipoarabinomannan (LAM). In the case of Man-LAM, which is found in Mycobacterium tuberculosis and other pathogenic species of mycobacteria, the carbohydrates are mannose groups. Ara-LAM is not capped and it is found in non-pathogenic, fast growing strains of mycobacteria.

Trehalose

A disaccharide formed by two glucose units.

Siderophores

Low molecular-weight compounds that are secreted by numerous types of bacteria and that have a high affinity for iron and other metal ions. These molecules chelate metal ions and carry them into the cell through specific receptors. They are bacterial virulence factors.

Sphingosine

An amino alcohol that can be linked to a fatty acid via the amino group to form the basic structure of sphingolipids.

Purified protein derivative

A protein from Mycobacterium tuberculosis that is used in the tuberculin sensitivity test, which determines previous interactions of the host with the bacterium. A positive tuberculin test is generally taken as an indication of previous exposure to M. tuberculosis.

α-Galactosylceramide

(α-GalCer). A synthetic or marine-sponge-derived glycolipid containing an α-anomeric glycosidic linkage of the galactose residue to the sphingosine base. This lipid, and structurally related ones, potently activates CD1 d-restricted natural killer T cells that express the semi-invariant Vα14–Jα18 T-cell receptor in mice (and the Vα24–Jα18 equivalent receptor in humans).

Lyme disease

A disease caused by the bacterium Borrelia burgdorferi or other Borrelia spp. that is transmitted to humans via the bites of infected blacklegged ticks. Symptoms can include skin rash, fever, fatigue, headache, muscle pain, stiff neck and swelling of the knee and other large joints. Most cases can be successfully treated with antibiotics.

Globo/isoglobo-series glycosphingolipids

One arm of the glycosphingo-lipid family, which is characterized by an α-linked galactose sugar in the third sugar position. Globotrihexo-sylceramide (Gb3) has an α1–4 linked galactose sugar, whereas isoglobotrihexosylceramide (iGb3) has an α1–3 linked galactose sugar.

Signal sequences

Short peptide sequences involved in the post-translational targeting of proteins. In particular, the endoplasmic reticulum (ER) signal sequence is recognized by the signal-recognition peptide after synthesis of the signal and the protein is co-translationally inserted into the ER lumen. The signal sequence is normally removed by a signal peptidase.

Secretory pathway

A trafficking pathway from the endoplasmic reticulum to the plasma membrane that is taken by newly synthesized molecules that are destined to be secreted.

Chylomicrons

Large lipoprotein particles primarily composed of triglycerides, secreted by the intestine into the lymphatic system and degraded by lipoprotein lipase.

Endoglycosidase-H resistance

Endoglycosidase H cleaves high-mannose oligosaccharides from N-linked glycoproteins. The acquisition of resistance to this enzyme is related to the processing of the high mannose into complex oligosaccharides in the medial Golgi apparatus and therefore indicates progression through the secretory pathway.

Invariant chain

(Ii). A non-polymorphic molecule that associates with MHC class II proteins. By occupying the antigen-binding cleft, the invariant chain stabilizes newly synthesized MHC class II molecules in the endoplasmic reticulum and directs the mature molecules to compartments in which binding with antigenic peptides occurs.

Surface plasmon resonance

A technique used to measure molecular interactions by observing how much of an input molecule (for example, a protein) is bound to a chip immobilized with another molecule. The amount of bound input is directly proportional to the change in the light reflected off the immobilized chip, which is specifically measured. This technique can be used to calculate single-molecule affinities, as well as binding on and off rates.

Slow recycling pathway

One arm of the early recycling pathway that involves trafficking through early endosomes and the endocytic recycling compartment.

Pinocytosis

A type of endocytosis in which fluid is taken up by cells.

C-type lectins

Receptor proteins that bind carbohydrates in a calcium-dependent manner. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved between members of this family.

Langerhans cells

A type of dendritic cell that is resident in the epidermal layer of the skin.

Class-II-associated invariant chain peptide

(CLIP). A fragment of invariant chain that occupies the MHC class II antigen-binding groove and prevents loading of antigenic peptides.

Metachromatic leukodystrophy

An inherited lipid storage disorder that affects the growth and/or development of the myelin sheet. Although several cell types can be affected, the pathology is essentially associated with the nervous system. This disease has infantile, juvenile and adult forms.

Gaucher's disease

A heterogeneous genetic lipid storage disorder. The most common form, type 1, is characterized by anaemia, low platelet counts, enlarged liver and spleen and skeletal disorders and may involve lung and kidney impairment.

Toll-like receptor

(TLR). A family of pattern-recognition receptors that recognize conserved molecules from pathogens, such as lipopolysaccharide or endotoxin, initiating innate immune responses.

Spirochetes

Phylum of flagellated helical-shaped, Gram-negative bacteria.

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Barral, D., Brenner, M. CD1 antigen presentation: how it works. Nat Rev Immunol 7, 929–941 (2007). https://doi.org/10.1038/nri2191

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