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  • Review Article
  • Published:

Recognition of lipid antigens by T cells

Nature Reviews Immunology volume 5, pages 485–496 (2005)Cite this article

Key Points

  • Lipid antigens are immunogenic for T cells when they are presented by CD1 antigen-presenting molecules that bind lipids. Five CD1 proteins are expressed in humans, whereas only one is expressed in mice.

  • Lipid molecules are not soluble in water and are always associated with membranes or lipid-binding proteins in tissues and biological fluids. This characteristic makes the biology and immunogenicity of lipids different from that of peptides. Microbial and self lipid antigens have been identified.

  • Intracellular microorganisms that infect antigen-presenting cells and localize in the phagosomes release immunogenic lipids, which travel to the compartments where they intersect with recycling CD1 molecules.

  • Complex glycolipids become stimulatory after processing and loading onto CD1 molecules in endosomal compartments. Both of these events are assisted by lipid-transfer proteins, which are necessary and redundant.

  • Lipid-specific T cells can use both T-cell receptor (TCR)-αβ and TCR-γδ, do not preferentially express CD4 or CD8 co-receptors, are selected intrathymically, and are primed in the periphery. Recall lipid-specific T-cell responses are observed after microbial infections.

  • Lipid-specific T cells release either T helper 1 (TH1)- or TH2-type cytokines, and might have regulatory functions. They therefore participate in immune responses with the same qualification as peptide-specific T cells.

  • The response to lipid antigens is associated with previous or ongoing bacterial infections, the recognition of tumour cells and the control of autoimmunity.

Abstract

Recent studies have shown that the recognition of lipid antigens by the immune system is important for defence against infection and other diseases, and that lipid-specific responses occur at higher frequencies than previously suspected. Thanks to several recent advances in this field, we now have a better appreciation of the molecular and cellular requirements of T-cell stimulation by lipids. These findings have raised new questions about the mechanisms of lipid presentation, the priming and clonal expansion of lipid-specific T cells, and their differentiation into memory cells. A greater understanding of lipid-specific T cells and the molecular mechanisms of lipid immunogenicity should facilitate the development of lipid-based vaccines.

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Figure 1: Structures of representative bacterial antigenic lipids.
Figure 2: Structures of representative self-antigenic lipids.
Figure 3: Lipid uptake and processing.
Figure 4: Intracellular trafficking of CD1 molecules.
Figure 5: Lipid loading on CD1 molecules.

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Acknowledgements

We thank all the members of our laboratory for their dedication and enthusiasm, T.-J. Resink and E. Palmer for discussions and reading of the manuscript, and A. Bendelac and M. Kronenberg for sharing data before publication. We apologize to those whose work has not been included. Our laboratory is supported by the University Hospital Basel, the Swiss National Science Foundation, the European Community and the Swiss Multiple Sclerosis Foundation.

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Authors and Affiliations

  1. Department of Research, Experimental Immunology, University Hospital, Basel, 4031, Switzerland

    Gennaro De Libero & Lucia Mori

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  1. Gennaro De Libero
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Correspondence to Gennaro De Libero.

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DATABASES

Entrez Gene

CD1a

CD1b

CD1c

CD1d

CD1e

GM2A

MTP

OMIM

leprosy

multiple sclerosis

psoriasis

rheumatoid arthritis

systemic lupus erythematosus

tuberculosis

FURTHER INFORMATION

Cyberlipid Center

De Libero's Group

The Lipid Library

Glossary

MULTIPLE SCLEROSIS

(MS). A chronic inflammatory and demyelinating disease of the central nervous system. MS is characterized by an autoimmune response against components of myelin, which is thought to contribute to disease pathogenesis. Self glycolipids are autoantigens that are recognized by T cells in this disease.

SIDEROPHORES

Numerous bacteria secrete these low molecular-weight compounds, which 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 represent bacterial virulence factors.

CROSSPRIMING AND CROSSPRESENTATION

Mechanisms by which a professional antigen-presenting cell primes or activates a T cell that is specific for an antigen derived from a third cell type.

EXOSOMES

Minute natural membrane vesicles that are secreted by various types of cells in the immune system.

INVARIANT CHAIN

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.

LIPID-TRANSFER PROTEINS

(LTPs). Proteins with hydrophobic features (pockets and binding regions). LTPs bind lipids and facilitate the solubilization, transport and interaction of lipids with other proteins.

TRANSLOCASE

A lipid translocase is an ATP-dependent flippase that facilitates the unidirectional movement of lipids from one membrane leaflet to the other. Translocases contribute to asymmetrical lipid distribution across the bilayer.

PHAGOSOME

The functional definition of the organelle in which bacteria are internalized. Virulent bacteria inhibit the acidification of the phagosome and its fusion with lysosomes. This is an important escape mechanism that facilitates bacterial intracellular growth.

FLIPPASE

A protein or protein complex that facilitates the energetically unfavourable movement of the polar head group of a phospholipid or glycosphingolipid through the hydrophobic interior of a membrane.

SCRAMBLASE

An energy-independent bidirectional lipid flippase that, when activated by transient rises in intracellular Ca2+ levels, disrupts lipid asymmetry and facilitates the fast equilibration of lipids between the two membrane leaflets.

COMPLEMENTARITY DETERMINING REGION 3

(CDR3). The antigen-receptor region (in T- and B-cell receptors) that interacts with the antigen, in which hypervariable sequences are located. CDR3 is partly encoded by the germline variable (V), diversity (D) and joining (J) regions of each receptor chain. Extensive diversity is generated during gene rearrangement by nucleotide trimming and/or template-independent nucleotide additions by terminal deoxynucleotidyl transferase.

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De Libero, G., Mori, L. Recognition of lipid antigens by T cells. Nat Rev Immunol 5, 485–496 (2005). https://doi.org/10.1038/nri1631

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