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T‐Cell Recognition of Non‐Protein Antigens

T‐Cell Recognition of Non‐Protein Antigens
CD1 presents lipid, glycolipid, and lipoprotein antigens
After MHC class I and class II, the CD1 family (CD1a–e) of molecules comprise a third set of antigen‐presenting molecules recognized by T‐lymphocytes. Just like the MHC class I α chain, CD1 associates with β2‐microglobulin, and the overall structure is indeed similar to that of classical class I molecules, although the topology of the binding groove is altered (see Figure 4.29). CD1 molecules can present (Figure 5.25) a broad range of lipid, glycolipid, and lipopeptide antigens, and even certain small organic molecules, to clonally diverse αβ and γδ T‐cells and, for CD1d, to NKT cells.

Figure 5.25 The processing and presentation of lipid antigens. The CD1 molecules containing self lipid transit to the cell surface (where they may be able to stimulate selfreactive Tcells). Subsequently the CD1 molecules are internalized into clathrin coated pits and can be recycled to meet with the endocytic pathway. Some CD1 molecules may also be directly sent to meet up with the endosomes, bypassing a preliminary cell surface step. Newly synthesized CD1 molecules in the endoplasmic reticulum (ER) can incorporate self lipids in a process mediated by the microsomal triglyceride transfer protein (MTP). One route for the presentation of exogenous lipid antigens involves the exchange of self and foreign lipid antigen in endosomal compartments. Lipidcontaining pathogen antigens are taken up by the cell, either by receptormediated (e.g., by low density lipoprotein receptor, C type lectin receptors or scavenger receptors) or by general uptake. Enzymemediated processing of these foreign antigens can take place in the late endosomes and, following fusion with the transGolgi vesicle containing the CD1 and self lipid, saposinmediated exchange of the foreign and self lipid can occur. The foreign lipidcontaining CD1 is then taken to the cell surface for recognition by αβ Tcells, γδ Tcells, or NKT cells bearing an appropriate TCR.

Figure 5.26 The CD1 antigenbinding pocket. In this example the binding of phosphatidylinositol (Ptdins) to CD1b is shown with the binding pocket represented from a top view, looking directly into the groove. Aliphatic backbones are in green, phosphor atom in blue, and oxygen atoms in red. (Source: Hava D.L. et al. (2005) Current Opinion in Immunology 17, 88–94. Reproduced with permission of Elsevier.)

A common structural motif facilitates CD1‐mediated antigen presentation and comprises a hydrophobic region of a branched or dual acyl chain and a hydrophilic portion formed by the polar or charged groups of the lipid and/or its associated carbohydrate or peptide. In a solved crystal structure the hydrophobic regions are buried in the deep binding groove of CD1b, while the hydrophilic regions, such as the carbohydrate structures, are recognized by the TCR (Figure 5.26). In another solved structure, the αβ TCR recognizes CD1d plus α‐galactosylceramide by docking in parallel to the complex (Figure 5.27). This is rather different to the diagonal or orthogonal binding usually seen with αβ TCR recognition of peptide–MHC (Figure 5.28).

Figure 5.27 Tcell receptor (TCR) recognition of CD1dpresented antigen. αβ TCR recognition of αgalactosylceramide presented by CD1d. The α1 (colored cyan) and α2 (magenta) regions of CD1d and the glycolipid (yellow) are shown, together with the CDR loops of the TCR α and β chains. Note the TCR binding is towards one end of the CD1d molecule. Because the lipid component of the antigen is buried within the CD1d molecule, recognition of αgalactosylcera- mide by the TCR involves only the protruding glycosyl head. The TCR α chain CDR1 (α1) interacts only with the antigen, whereas the α chain CDR3 (α3) interacts with both the antigen and CD1d. Recognition of the antigen does not involve the TCR β chain, whose CDR2 (β2) and CDR3 (β3) bind to CD1d. The α chain CDR2 (α2) and β chain CDR1 (β1) are not involved in binding to the CD1d–anti- gen complex in this example. (Source: Marrack P. et al. (2008) Annual Review of Immunology 26, 171–203. Reproduced with ssion of Annual Reviews.).
Figure 5.28 Comparison of TCR recognition of CD1d–lipid and MHC–peptide. (a) Tcell receptor (TCR) αchain (yellow) and βchain (blue) binding to αgalactosylceramide (magenta) presented by CD1d (green). (b) TCR αchain (purple) and βchain (cyan) binding to MHC (gray) and peptide (magenta). (c) Parallel docking mode seen with TCR (CDR1α, yellow; CDR2α, green; CDR3α, cyan; CDR1β, magenta; CDR2β, orange; CDR3β, blue) recognition of αgalactosylceramide (magenta) presented by CD1d (αhelices, pale green). (d) Diagonal docking mode of a typical TCR (CDR loops colored as in (c)) with peptide–MHC. In (c) and (d) the center of mass between the Vα and Vβ domain is indicated by the black line,

Both endogenous and exogenous lipids can be presented by CD1 (Figure 5.25) and, like MHC class I, the CD1 heavy chain complexes initially with calnexin in the endoplasmic reticulum and is then subsequently replaced with calreticulin. The protein ERp57 is then recruited into the complex. Subsequent dissociation of the complex permits the binding of β2‐microglobulin and, in a step involving the microsomal triglyceride transfer protein (MTP), the insertion of endogenous lipid antigens into the CD1 antigen‐binding region. Just like their proteinaceous colleagues, exogenously derived lipid and glycolipid antigens are delivered to the acidic endosomal compartment. Both humans and mice deficient in prosaposin, a precursor molecule of the sphingolipid activator proteins (SAPs) saposin A–D, are defective in the presentation of lipid antigens to T‐cells. Various lines of enquiry indicate that these molecules are involved in the transfer of lipid antigens to CD1 in the endosomes (Figure 5.25). Ligands for CD1a include the sulfatide sphingolipid and mycopeptides such as didehydroxymycobactin from Mycobacterium tuberculosis; those for CD1b are mycolic acid and carbohydrate structures, such as the mycobacterial cell wall component lipoarabinomannan; and those for CD1c include mycobacterial mannosyl‐1‐phosphodolichol. The α‐galactosylceramide from marine sponges is known to be a very potent stimulator of invariant NKT (iNKT) cells when presented by CD1d. Microbial lipids presented by CD1d include Borrelia burgdorferi α‐galactosyl diacylglycerol, whereas endogenous lipids such as lysophosphatidylcholine presented by this member of the CD1 family may act as markers of inflammation. The fifth member of the family, CD1e, has very distinct properties and may function rather like saposin as a lipid exchange facilitator for CD1b and CD1c to permit the rep acement of endogenous lipid with those of microbial origin.

NKT cells
NKT cells possess the NK1.1 marker, characteristic of NK cells, together with a T‐cell receptor. There are two populations, one with diverse TCRs and the other referred to as invariant NKT‐cells (iNKT cells). In the latter population the TCR bears an invariant α chain (Vα24Jα18 in humans, Vα14Jα18 in mice) with no N‐region modifications and an extremely limited β chain repertoire based upon Vβ11 in the human and Vβ8.2, Vβ7, and Vβ2 in the mouse. They recognize lipid antigens presented by CD1d and constitute a major component of the T‐cell compartment, accounting for approximately 30% of the T‐cells in the liver (and up to 2.5% of T‐cells in the seconday lymphoid tissues) in mice. Although iNKT cells are present at a much lower frequency in humans, the NKT population with diverse receptors is much more prevalent in humans than in mice. Upon activation, NKT cells rapidly secrete IL‐4 and IFNγ and thereby can be involved in the stimulation of many cell types, including dendritic cells, NK cells, and B‐cells.