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 self‐reactive T‐cells). 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. Lipid‐containing pathogen antigens are taken up by
the cell, either by receptor‐mediated (e.g., by low density lipoprotein
receptor, C‐ type lectin receptors or scavenger receptors)
or by general uptake. Enzyme‐mediated processing of these foreign antigens
can take place in the late endosomes and, following fusion with the trans‐Golgi vesicle containing the CD1 and self lipid, saposin‐mediated exchange of the foreign and self lipid can occur. The foreign
lipid‐containing CD1 is then taken to the cell
surface for recognition by αβ T‐cells, γδ T‐cells, or NKT cells bearing an appropriate
TCR.
 |
Figure 5.26 The CD1 antigen‐binding 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 T‐cell receptor (TCR) recognition of CD1d‐presented antigen. αβ TCR recognition of α‐galactosylceramide 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 α‐galactosylcera- 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) T‐cell receptor (TCR) α‐chain (yellow) and β‐chain (blue) binding to α‐galactosylceramide (magenta) presented by CD1d (green). (b) TCR α‐chain (purple) and β‐chain (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 α‐galactosylceramide (magenta) presented by CD1d (α‐helices, 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.
