TCR binds microbial lipid-based antigen via CD1

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Reaction [binding]
Homo sapiens
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The hallmark of T cell activation is the direct binding of T-cell receptor (TCR) to an antigen that is presented by an antigen-presenting molecule. TCRs are able to recognize as antigens a large variety of molecules including peptides, lipids, and vitamin metabolites (Moody DB et al. 2005; Rossjohn J et al. 2015; de Jong A 2015). While TCR responds to peptides when they are presented by classical major histocompatibility complex (MHC)-encoded class I or II molecules, specific recognition of lipids by TCR occurs when lipid-based antigens form antigenic complexes with CD1 antigen-presenting molecules (Garboczi DN et al. 1996; Beckman EM et al. 1994; De Libero G1 & Mori L 2005; Tatituri RV et al. 2013; Van Rhijn I et al. 2015).

Humans express five functional CD1 isotypes (CD1a-e), with CD1e being the only member that does not directly present antigens to T cells (Calabi F et al. 1989; Balk SP et al. 1989; de la Salle H et al. 2005). CD1a, CD1b, CD1c and CD1d are surface expressed proteins that can be found on the plasma membranes of antigen-presenting cells (APC) (Dougan SK et al. 2007). CD1 ectodomains consist of a heavy chain, which folds into three extracellular domains (alpha1, alpha2 and alpha3) noncovalently associated with beta2-microglobulin (B2M) (Moody DB et al. 2005). Antigen-binding grooves nestle between the alpha1 and alpha2 helices and are mostly lined by hydrophobic residues (Zeng Z et al. 1997). This allows the antigenic lipids to be anchored via their hydrophobic chains, so that polar motifs protrude toward the aqueous milieu (Gadola SD et al. 2002; Zajonc DM et al. 2003, 2005; Batuwangala T et al. 2004; Koch M et al. 2005; Zajonc DM et al. 2005; Scharf L et al. 2010; Garcia-Alles LF et al. 2011). Consequently, polar heads establish stimulatory contacts with TCRs, while variation in the number, length and saturation of alkyl chains may contribute to the binding to varying degrees (Borg NA et al. 2007; Garcia-Alles LF et al. 2011; Li Y et al. 2010; Pei B et al 2012; Pierce BG et al. 2014). Each of the four CD1 isoforms that directly present antigens to T cells differ in size of the antigen-binding grooves (Zajonc DM et al. 2005; Gadola SD et al. 2002; Zajonc DM et al. 2003, 2005; Batuwangala T et al. 2004; Koch M et al. 2005; Cheng TY et al. 2006; Borg NA et al. 2007; Scharf L et al. 2010; Garcia-Alles LF et al. 2011), intracellular trafficking patterns (Sugita M et al. 1999; Moody DB & Porcelli SA 2003), lipid ligand repertoire (Im JS et al. 2004; Huang S et al. 2011; Ly D & Moody DB 2014), and tissue distribution of expression (Dougan SK et al. 2007). Together with the observation that multiple CD1 isoforms have been maintained throughout mammalian evolution, this argues that each CD1 isoform plays a non-redundant role in the immune system (Dascher CC 2007; de Jong A 2015).

T cells recognize both endogenous and exogenous (derived from intracellular microbial pathogens) lipid antigens bound to CD1 molecules (Mattner J et al. 2005; Kinjo Y et al. 2005; Chang DH et al. 2008; Cohen NR et al. 2009; De Libero G et al. 2009; Zajonc DM & Girardi E 2015; Birkinshaw RW et al. 2015; de Jong A 2015). Foreign lipid antigens are extremely diverse chemically and include naturally occurring lipopeptide, glycolipids and phospholipid structures that are distinct from mammalian lipids (Moran A 2009). The best studied lipid antigens of microbial origin are glycolipids derived from the cell envelope of Mycobacteria species (De Libero G et al. 2009). They include CD1b-restricted foreign lipid antigens such as lipoarabinomannan (LAM), lipomannan (LM), phosphatidylinositol mannosides (PIM), mycolic acid, glucose monomycolate (GMM), glycerol monomycolate and diacylated sulpholipids (Sieling PA et al. 1995; Moody DB et al. 2000; Layre E et al. 2009; Gilleron M et al. 2004; Kasmar AG et al. 2011). While most mammalian glycolipids have beta-linked carbohydrates attached to the lipid backbone, bacterial glycolipids typically have alpha-linkage. The structural difference in the linkage may contribute to the highly specific interaction of the TCR with the CD1:lipid antigen complex thus dictating the outcome of the immune response (Scott-Browne JP et al. 2007; Zajonc DM et al. 2005, 2007). In addition, lipopeptides, such as didehydroxymycobactin (DDM), an intermediate in the biosynthesis of the mycobacterial iron scavenger mycobactin siderophores, can be recognized by CD1a-restricted T cells (Moody DB et al. 2004; Zajonc DM et al. 2005). Diacylglycerols, such as the alpha-galactosyldiacylglycerol from the spirochete Borrelia burgdorferi or an alpha-linkage glycosphingolipid (alpha-glucuronosylceramide) found in alpha-proteobacteria can be presented by CD1d to stimulate invariant natural killer T (iNKT) cells (Sriram V et al. 2005; Kinjo Y et al. 2006). The ability of T cells to see lipid antigens bound to CD1 proteins enables these lymphocytes to sense changes in the lipid composition of cells and tissues as a result of infections or inflammation (Mattner J et al. 2005; Kinjo Y et al. 2005; Chang DH et al. 2008; Cohen NR et al. 2009; de Jong A 2015).

The Reactome event shows foreign lipid-based molecules that have been reported to function as antigens for CD1-restricted T cells (Batuwangala T et al. 2004; Roy S et al. 2014; Garcia-Alles LF et al. 2011; Wang J et al. 2010; Sieling PA et al. 1995; Guiard J et al. 2009; Kasmar AG et al. 2011).

Literature References
PubMed ID Title Journal Year
26300885 Recognition of Microbial Glycolipids by Natural Killer T Cells

Girardi, E, Zajonc, DM

Front Immunol 2015
7542404 CD1-restricted T cell recognition of microbial lipoglycan antigens

Bloom, BR, Prigozy, TI, Kronenberg, M, Brennan, PJ, Soriano, T, Brenner, MB, Mazzaccaro, RJ, Chatterjee, D, Porcelli, SA, Sieling, PA

Science 1995
15864273 Anatomy of CD1-lipid antigen complexes

Moody, DB, Zajonc, DM, Wilson, IA

Nat. Rev. Immunol. 2005
18037897 CD1 antigen presentation: how it works

Barral, DC, Brenner, MB

Nat. Rev. Immunol. 2007
25703557 CD1 and mycobacterial lipids activate human T cells

Moody, DB, van Rhijn, I

Immunol. Rev. 2015
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