The αβ T‐cell receptor binds to a combination
of MHC and peptide
When soluble TCR
preparations produced using recombinant DNA technology are immobilized on a
sensor chip, they can bind MHC–peptide complex specifically with rather low
affinities (Ka) in the 104–107 M−1
range. This low affinity and the relatively small number of atomic contacts
formed between the TCRs and their MHC–peptide ligands when T‐cells contact
their target cell make the contribution of TCR recognition to the binding
energy of this cellular interaction fairly trivial. The brunt of the attraction
rests on the antigen‐independent major adhesion molecule pairs, such as LFA‐1 −
ICAM‐1 and CD2 − LFA‐3 that are recruited into the immunological synapse (see Figure 7.20), but any subsequent triggering of
the T‐cell by MHC–peptide antigen must involve signaling through the T‐cell receptor.
Topology of the ternary complex
Of the three complementarity
determining regions present in each TCR chain, CDR1 and CDR2 are much less
variable than CDR3. Unlike immunoglobulins, somatic hypermutation does not
occur in TCR genes, so variability in CDR1 and CDR2 is limited by the number of
germline V genes. However, just like in immunoglobulin, the TCR CDR3 is encoded
by a V(D)J sequence that results from combinatorial and nucleotide insertion mechanisms.
As the MHC sequences in a given individual are fixed, whereas there will be a
large number of different peptide sequences, a logical model would have CDR1
and CDR2 of each TCR chain contacting the α‐helices at the tip of the MHC
peptide‐binding groove, and the much more variable CDR3 contacting the peptide.
In accord with this view, several studies have shown that T‐cells that
recognize small variations in a peptide in the context of a given MHC molecule differ only in their CDR3 regions.
The combining sites of the
TCRs are generally relatively flat (Figure
5.21), which would
be expected given the need for complementarity to the gently
undulating surface of the peptide–MHC combination (Figure
5.22a). In most of the structures so far solved, recognition
involves the TCR lying either diagonally (Figure 5.22b) or orthogonally (Figure 5.22c) across the peptide–MHC with the TCR Vα CDR1 and CDR2 overlying the MHC class II β1‐helix or class I α2‐helix, and the Vβ CDR1 and CDR2 overlying the α1‐helix of MHC class I or class II (Figure 5.23). The more variable CDR3
regions make contact
with the peptide,
particularly focusing in on the middle residues (P4 to P6).
There is evidence to suggest that the TCR initially binds to the MHC in a fairly peptide‐independent fashion, followed by conformational changes particularly in the peptiderecognizing CDR3 loops of the TCR to permit optimal contact with the peptide. Activation through the TCR‐CD3 complex can operate if these adjustments permit more stable and multimeric binding. The CD4 or CD8 co‐receptor for MHC binds to nonpolymorphic residues present in the α2 and β2 domains of class II (Figure 5.24), and in the
α3 domain of class I,
respectively.
 |
Figure 5.22 Complementarity between MHC–peptide and T‐cell receptor. (a) Backbone structure of a TCR (2C) recognizing a peptide
(called dEV8) presented by the MHC class I molecule H‐2Kb. The TCR is in the top half of the picture, with the α chain in pink and its CDR1 colored magenta,
CDR2 purple, and CDR3 yellow. The β chain is colored light blue with its CDR1 cyan, CDR2 navy blue, CDR3
green, and the fourth hypervariable loop orange. Below the TCR is the MHC α chain in green and β2‐microglobulin in dark green.
The peptide with side‐chains at positions P1, P4, and P8 is colored
yellow. (Source: (a) Garcia K.C. et al. (1998) Science 279,
1166–1172.). (b) The same complex looking down onto a molecular surface
representation of the H‐2Kb in yellow, with the diagonal docking mode
of the TCR in a backbone worm representation colored pink. The peptide is drawn
in a ball and stick format. (c) By contrast, here we see the orthogonal docking
mode of a TCR (called D10) recognizing a conalbumin‐derived peptide presented by MHC class II. The TCR backbone worm
representation shows the Vα in green and Vβ in blue, and the I‐Ak class II molecular surface representation
has the α chain in light green and the β chain in orange, holding the peptide.
(Source: (b,c) Reinherz E.L. et al. (1999) Science 286,
1913–1921. Reproduced with on of AAAS.)
 |
Figure 5.23 TCR CDR3 recognition of peptide presented by
MHC. (a) Contacts between the CDR1–3 loops of the α and β chains of a T‐cell receptor (TCR) and a space‐filling surface of MHC and peptide. The example shown here is a mouse TCR
bound to the H2 I‐Ab presenting a 13‐mer peptide. The α1 region of MHC is colored cyan, the β1 or α2 region of MHC magenta and the peptide yellow. The CDR loops of the TCR α and β chains are indicated (α1
is CDR1 of the α chain, and so on). (b) Elevation perspective
of the interactions. (Source: Marrack P. et al. (2008) Annual Review
of Immunology 26, 171–203. Reproduced with permission
of Annual Reviews.)
 |
Figure 5.24 The TCR–peptide–MHC–CD4 complex. Ribbon diagram
of the complex oriented as if the TCR (MS2–3C8) and CD4 molecules are attached
to the T‐cell at the bottom and the MHC class II molecule
(HLA‐DR4) is attached to an opposing APC at the
top. TCR α chain, blue; TCR β chain, green; CD4, pink; MHC α chain, gray; MHC β chain, yellow; peptide (derived from myelin
basic protein), red. (Source: Yin Y. et al. (2012) Proceedings of the
National Academy of Sciences of the USA. 109, 5405–5410. Reproduced
with permission.)
MHC class I‐like molecules
In addition to the highly
polymorphic classical MHC class I molecules (HLA‐A, ‐B, and ‐C in the human and
H‐2 K,‐D, and ‐L in the mouse), there are other loci encoding peptide‐
presenting MHC molecules containing β2‐microglobulin with relatively
nonpolymorphic heavy chains. These are H‐2 M3,‐Qa,
and ‐Q in mice, and HLA‐E, ‐F, and ‐G
in humans.In addition there are a number of specialized MHC homologs,
including the T10 and T22 molecules which act as ligands for γδ T‐cells, that
do not present peptides and are present in mice but not in humans.
The H‐2 M3 molecule
is unusual in that its peptide‐binding groove has many nonpolar amino acids
designed to facilitate the binding of the characteristic hydrophobic N‐formylmethionine
residue of peptides derived from bacterial proteins, which can then be
presented to T‐cells. Expression of H‐2 M3 is
limited by the availability of these peptides so that high levels are only seen
during prokaryotic infections. Discussion of the role of HLA‐G expression in
the human extravillous cytotrophoblast will arise in
Chapter 15.
