Glycolipid Presentation by CD1

Abstract

CD1 molecules constitute a family of nonpolymorphic, MHC class I‐like antigen‐presenting glycoproteins, which bind amphipathic lipid antigens and present them to T cells. These proteins are involved in presenting a broad range of self and foreign lipid antigens to variable T lymphocytes and natural killer T cells bearing a semi‐invariant T‐cell receptor (iNKT). It has become clear that the recognition of lipid antigens by T cells plays an important role in the detection and clearance of pathogens, immune response regulation and tissue surveillance.

Key Concepts

  • Self and microbial lipids and glycolipids are recognised by T cells.
  • Hydrophobic pockets of CD1 proteins allow lipid antigens to be loaded via their alkyl chains, while the hydrophilic part of the antigen is presented to T‐cell receptors.
  • CD1 proteins are non‐polymorphic and predominantly expressed on the surface of antigen‐presenting cells.
  • Glycolipids can be processed into smaller antigenic structures in the endosomal pathway.
  • CD1e, a soluble protein found in late endosomes, assists in lipid antigen editing and loading onto other CD1 proteins.
  • CD1‐restricted T cells express αβ or γδ TCR and are found in CD4+, CD8+ or double‐negative T‐cell populations.
  • The frequency of autoreactive T cells is high among CD1‐restricted T cells.

Keywords: lipid; glycolipid; antigen; CD1; presentation; processing; saposin; endosome; lymphocyte T; Mycobacterium tuberculosis

Figure 1. Overview of lipid antigen presentation by CD1 proteins. Following their biosynthesis, CD1a, b, c and d are expressed at the surface of antigen‐presenting cells before being recycled to different endosomal compartments, in which they encounter lipids acquired from extracellular sources. Late endosomes and lysosomes are acidic compartment rich in accessory proteins and enzymes, facilitating the editing of lipid antigens and the loading of CD1 binding sites with these antigens.
Figure 2. Structural characteristics of CD1 proteins. (a) Structure of the CD1b protein – lateral view (left), and a corresponding top view (right). Three extracellular domains of CD1b (α1, α2 and α3) noncovalently associate with β2 microglobulin (β2m) (light gray). Domains engaged in antigen binding are shown in colour: α1 – red, α2 – green. The walls of the antigen binding groove are formed by helices and the floor consists of a β‐sheet. (b) Schematic representation of the mode of binding of the amphipathic antigen within the CD1b groove. (c) Summary of the major structural features of individual CD1 molecules.
Figure 3. The structural diversity of lipid antigens presented by CD1 proteins. CD1 isoforms present lipid antigens with diverse hydrophobic and head group moieties.
Figure 4. Processing of PIM antigens and their loading onto CD1 proteins. CD1e, exclusively found in late endosome and lysosome, is an accessory protein of the lipid antigens processing. CD1e facilitates the enzymatic modification of lipid antigens and their loading onto CD1 proteins by acting as a lipid transfer protein.
Figure 5. CD1‐restricted T‐cell functions. CD1‐restricted T cells contribute to immune responses by producing cytokines and exerting cytotoxicity mediated by the release of perforin and granulysin. Group 1 and 2 CD1‐restricted T cells include self‐reactive T cells and T cells specifically recognising microbial lipids. iNKT cells, constituting a major population of CD1d‐restricted T cells, are innate‐like T lymphocytes activated during microbial infection, through either the TCR‐mediated direct recognition of the CD1d‐microbial lipid complex or indirectly, by the cytokine environment generated by innate immune cells.
close

References

Angenieux C , Salamero J , Fricker D , et al. (2000) Characterization of CD1e, a third type of CD1 molecule expressed in dendritic cells. The Journal of Biological Chemistry 275: 37757–37764.

Batuwangala T , Shepherd D , Gadola SD , et al. (2004) The crystal structure of human CD1b with a bound bacterial glycolipid. Journal of Immunology 172: 2382–2388.

Beckman EM , Porcelli SA , Morita CT , et al. (1994) Recognition of a lipid antigen by CD1‐restricted alpha beta+ T cells. Nature 372: 691–694.

Birkinshaw RW , Pellicci DG , Cheng TY , et al. (2015) alphabeta T cell antigen receptor recognition of CD1a presenting self lipid ligands. Nature Immunology 16: 258–266.

Bourgeois EA , Subramaniam S , Cheng TY , et al. (2015) Bee venom processes human skin lipids for presentation by CD1a. The Journal of Experimental Medicine 212: 149–163.

Bricard G and Porcelli SA (2007) Antigen presentation by CD1 molecules and the generation of lipid‐specific T cell immunity. Cellular and Molecular Life Sciences: CMLS 64: 1824–1840.

Brigl M and Brenner MB (2004) CD1: antigen presentation and T cell function. Annual Review of Immunology 22: 817–890.

Brigl M , Bry L , Kent SC , Gumperz JE and Brenner MB (2003) Mechanism of CD1d‐restricted natural killer T cell activation during microbial infection. Nature Immunology 4: 1230–1237.

Briken V , Jackman RM , Dasgupta S , Hoening S and Porcelli SA (2002) Intracellular trafficking pathway of newly synthesized CD1b molecules. The EMBO Journal 21: 825–834.

Brozovic S , Nagaishi T , Yoshida M , et al. (2004) CD1d function is regulated by microsomal triglyceride transfer protein. Nature Medicine 10: 535–539.

Cala‐De Paepe D , Layre E , Giacometti G , et al. (2012) Deciphering the role of CD1e protein in mycobacterial phosphatidyl‐myo‐inositol mannosides (PIM) processing for presentation by CD1b to T lymphocytes. Journal of Biological Chemistry 287: 31494–31502.

Cantu C , Benlagha K , Savage PB , Bendelac A , and Teyton L (2003) The paradox of immune molecular recognition of alphaαgalactosylceramide: low affinity, low specificity for CD1d, high affinity for alpha beta TCRs. Journal of Immunology 170: 4673–4682.

Darmoise A , Maschmeyer P and Winau F (2010) The immunological functions of saposins. Advances in Immunology 105: 25–62.

de Jong A , Cheng TY , Huang S , et al. (2014) CD1a‐autoreactive T cells recognize natural skin oils that function as headless antigens. Nature Immunology 15: 177–185.

de Jong A , Pena‐Cruz V , Cheng TY , et al. (2010) CD1a‐autoreactive T cells are a normal component of the human alphabeta T cell repertoire. Nature Immunology 11: 1102–1109.

de la Salle H , Mariotti S , Angenieux C , et al. (2005) Assistance of microbial glycolipid antigen processing by CD1e. Science 310: 1321–1324.

Lee PT , Benlagha K , Teyton L , and Bendelac A (2002) Distinct functional lineages of human V(alpha)24 natural killer T cells. The Journal of experimental medicine 195: 637–641.

de Lalla C , Lepore M , Piccolo FM , et al. (2011) High‐frequency and adaptive‐like dynamics of human CD1 self‐reactive T cells. European Journal of Immunology 41: 602–610.

Dougan SK , Kaser A and Blumberg RS (2007) CD1 expression on antigen‐presenting cells. Current Topics in Microbiology and Immunology 314: 113–141.

Dutronc Y and Porcelli SA (2002) The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60: 337–353.

Ernst WA , Maher J , Cho S , et al. (1998) Molecular interaction of CD1b with lipoglycan antigens. Immunity 8: 331–340.

Facciotti F , Cavallari M , Angenieux C , et al. (2011) Fine tuning by human CD1e of lipid‐specific immune responses. Proceedings of the National Academy of Sciences of the United States of America 108: 14228–14233.

Gadola SD , Zaccai NR , Harlos K , et al. (2002) Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains. Nature Immunology 3: 721–726.

Garcia‐Alles LF , Collmann A , Versluis C , et al. (2011a) Structural reorganization of the antigen‐binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids. Proceedings of the National Academy of Sciences of the United States of America 108: 17755–17760.

Garcia‐Alles LF , Giacometti G , Versluis C , et al. (2011b) Crystal structure of human CD1e reveals a groove suited for lipid‐exchange processes. Proceedings of the National Academy of Sciences of the United States of America 108: 13230–13235.

Garcia‐Alles LF , Versluis K , Maveyraud L , et al. (2006) Endogenous phosphatidylcholine and a long spacer ligand stabilize the lipid‐binding groove of CD1b. The EMBO Journal 25: 3684–3692.

Gilleron M , Stenger S , Mazorra Z , et al. (2004) Diacylated sulfoglycolipids are novel mycobacterial antigens stimulating CD1‐restricted T cells during infection with Mycobacterium tuberculosis. Journal of Experimental Medicine 199: 649–659.

Gumperz JE , Miyake S , Yamamura T , and Brenner MB (2002) Functionally distinct subsets of CD1d‐restricted natural killer T cells revealed by CD1d tetramer staining. The Journal of experimental medicine 195: 625–636.

Hiromatsu K , Dascher CC , Sugita M , et al. (2002) Characterization of guinea‐pig group 1 CD1 proteins. Immunology 106: 159–172.

Joyce S , Woods AS , Yewdell JW , et al. (1998) Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science 279: 1541–1544.

Kain L , Webb B , Anderson BL , et al. (2014) The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian alpha‐linked glycosylceramides. Immunity 41: 543–554.

Kasmar AG , van Rhijn I , Cheng TY , et al. (2011) CD1b tetramers bind alphabeta T cell receptors to identify a mycobacterial glycolipid‐reactive T cell repertoire in humans. The Journal of Experimental Medicine 208: 1741–1747.

Kasmar AG , Van Rhijn I , Magalhaes KG , et al. (2013) Cutting Edge: CD1a tetramers and dextramers identify human lipopeptide‐specific T cells ex vivo. Journal of Immunology 191: 4499–4503.

Kovalovsky D , Uche OU , Eladad S , et al. (2008) The BTB‐zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature immunology 9: 1055–1064.

Layre E , Collmann A , Bastian M , et al. (2009) Mycolic acids constitute a scaffold for mycobacterial lipid antigens stimulating CD1‐restricted T cells. Chemistry & Biology 16: 82–92.

Lepore M , de Lalla C , Gundimeda SR , et al. (2014) A novel self‐lipid antigen targets human T cells against CD1c(+) leukemias. Journal of Experimental Medicine 211: 1363–1377.

Ly D , Kasmar AG , Cheng TY , et al. (2013) CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. Journal of Experimental Medicine 210: 729–741.

Lynch L , Michelet X , Zhang S et al. (2015) Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nature immunology 16: 85–95.

Moody DB , Ulrichs T , Muhlecker W , et al. (2000) CD1c‐mediated T‐cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404: 884–888.

Moody DB , Young DC , Cheng TY , et al. (2004) T cell activation by lipopeptide antigens. Science 303: 527–531.

Mulcahy LA , Pink RC and Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. Journal of Extracellular Vesicles 3.

Prigozy TI , Naidenko O , Qasba P , et al. (2001) Glycolipid antigen processing for presentation by CD1d molecules. Science 291: 664–667.

Rossjohn J , Pellicci DG , Patel O , Gapin L , and Godfrey DI (2012) Recognition of CD1d‐restricted antigens by natural killer T cells. Nature reviews Immunology 12: 845–857.

Schaible UE , Winau F , Sieling PA , et al. (2003) Apoptosis facilitates antigen presentation to T lymphocytes through MHC‐I and CD1 in tuberculosis. Nature Medicine 9: 1039–1046.

Schiefner A and Wilson IA (2009) Presentation of lipid antigens by CD1 glycoproteins. Current Pharmaceutical Design 15: 3311–3317.

Tupin E , Kinjo Y and Kronenberg M (2007) The unique role of natural killer T cells in the response to microorganisms. Nature Reviews Microbiology 5: 405–417.

van den Elzen P , Garg S , Leon L , et al. (2005) Apolipoprotein‐mediated pathways of lipid antigen presentation. Nature 437: 906–910.

Van Rhijn I , Kasmar A , de Jong A , et al. (2013) A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nature Immunology 14: 706–713.

Van Rhijn I and Moody DB (2015a) CD1 and mycobacterial lipids activate human T cells. Immunological Reviews 264: 138–153.

Van Rhijn I , Young DC , De Jong A , et al. (2009) CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids. The Journal of Experimental Medicine 206: 1409–1422.

Winau f , Schwierzeck V , Hurwitz R , et al. (2004) Saposin C is required for lipid presentation by human CD1b. Nature immunology 5: 169–174.

Wu D , Zajonc DM , Fujio M , et al. (2006) Design of natural killer T cell activators: structure and function of a microbial glycosphingolipid bound to mouse CD1d. Proceedings of the National Academy of Sciences of the United States of America 103: 3972–3977.

Yuan W , Kang SJ , Evans JE and Cresswell P (2009) Natural lipid ligands associated with human CD1d targeted to different subcellular compartments. Journal of Immunology 182: 4784–4791.

Further Reading

Anderson BL , Teyton L , Bendelac A and Savage PB (2013) Stimulation of natural killer T cells by glycolipids. Molecules 18: 15662–15688.

Barral DC and Brenner MB (2007) CD1 antigen presentation: how it works. Nature Reviews Immunology 7: 929–941.

Bhati M , Cole DK , McCluskey J , Sewell AK and Rossjohn J (2014) The versatility of the alphabeta T‐cell antigen receptor. Protein Science: A Publication of the Protein Society 23: 260–272.

Cohen NR , Garg S and Brenner MB (2009) Antigen Presentation by CD1 Lipids, T Cells, and NKT Cells in Microbial Immunity. Advances in Immunology 102: 1–94.

De Libero G and Mori L (2014a) Professional differences in antigen presentation to iNKT cells. Immunity 40: 5–7.

De Libero G and Mori L (2014b) The T‐Cell Response to Lipid Antigens of Mycobacterium tuberculosis. Frontiers in Immunology 5: 219.

Dowds CM , Kornell SC , Blumberg RS and Zeissig S (2014) Lipid antigens in immunity. Biological Chemistry 395: 61–81.

Ly D and Moody DB (2014) The CD1 size problem: lipid antigens, ligands, and scaffolds. Cellular and Molecular Life Sciences: CMLS 71: 3069–3079.

Moody DB (ed) (2007) T Cell Activation by CD1 and Lipid Antigens, p. 345. Berlin Heidelberg: Springer‐Verlag.

Van Rhijn I and Moody DB (2015b) CD1 and mycobacterial lipids activate human T cells. Immunological Reviews 264: 138–153.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Layre, Emilie, Mazurek, Jolanta, and Gilleron, Martine(Aug 2015) Glycolipid Presentation by CD1 . In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020182.pub2]