Page 75 - Clinical Immunology_ Principles and Practice ( PDFDrive )

60 Part one Principles of Immune Response

Rather than binding to a single groove on the MHC, lipids
Binding to pMHC attach themselves to one of several hydrophobic pockets that
TCRs recognize peptide antigens bound to the binding groove can be found on the surface of CD1. Pocket volume can range
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of MHC-encoded glycoproteins (see Fig. 4.3). TCR recognition from 1300 to 2200 Å . The number and length of the pockets
of pMHC requires a trimolecular complex in which all the differ between the various CD1 isoforms. For example, CD1b
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components (antigen, MHC, and TCR) contact one another. has three pockets that share a common portal of entry, as well
Thus recognition is highly influenced by polymorphisms in the as a fourth pocket that connects two of the three pockets to each
MHC molecule (Chapter 5). As in the case of Igs, TCR CDR1 other. This connecting pocket permits the insertion of lipids
and CDR2 are encoded in the germline V regions, whereas CDR3 with a long alkyl chain, such as mycobacterial mycolic acid.
is formed at the junction of the V gene with a J gene segment γδ T cells are activated by conserved stress-induced ligands,
(TCR α and γ) or D and J gene segments (TCR β and δ chains). enabling them to rapidly produce cytokines that regulate pathogen
Vβ also has a fourth region of variability within Framework 3 clearance, inflammation, and tissue homeostasis in response to
that is juxtaposed to the other CDRs in the tertiary structure. tissue stress. 21
This region, variously termed hypervariable region 4 (HV4) or Antigen recognition by γδ TCRs resembles recognition of
CDR4, can participate in SAg binding. intact antigens by antibodies more closely than recognition of
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The cocrystallization of different combinations of soluble pMHC by αβ TCR. γδ TCRs can recognize protein antigens,
TCR αβ interacting with MHC class I bound to antigen peptide such as nonclassic MHC molecules and viral glycoproteins, as
(pMHC) has made it possible to directly address the manner in well as small, phosphate- or amine-containing compounds, such
which antigen recognition occurs (see Fig. 4.3). The TCR αβ as pyrophosphomonoesters from mycobacteria and alkylamines.
combining site is relatively flat, allowing it to interact with a Binding to non-peptide antigens plays an important role in
rather broad surface at the point of contact with pMHC. the biology of γδ T cells. About 5% of peripheral blood T cells
The TCR footprint on the pMHC complex tends to occur in bear γδ TCRs, and most of these are encoded by Vγ9 JγP and
a diagonal across the MHC antigen-binding groove, with TCR Vδ2 gene segments. (In an alternative nomenclature, Vγ9 is known
Vα positioned over the MHC α 2 helix and TCR Vβ overlying as Vγ2 and JγP as Jγ1.2. See the IMGT database at http://
the MHC α 1 helix. This geometry would permit consistent access www.imgt.org.) These Vγ9 JγPVδ2 TCRs recognize nonpeptide
of the CD8 coreceptors to the MHC class I molecule. The CDR1 pyrophosphate- or amine-containing antigens, such as pyro-
and CDR2 loops, which are entirely encoded by germline sequence, phosphomonoesters from mycobacteria or isobutylamine from
tend to interact more with the MHC molecule, whereas the various sources. Other common naturally occurring small
CDR3 loops, which are composed of both germline and somatic phosphorylated metabolites that stimulate γδ T cells include
(N addition) sequences, appear to dominate the interaction with 2,3-diphosphoglyceric acid, glycerol-3-phosphoric acid, xylose-
the MHC-bound peptide. 1-phosphate, and ribose-1-phosphate. In addition to mycobacteria,
The binding of TCR to pMHC appears to be driven by Vγ9JγPVδ2 T-cell populations are seen to expand in response
enthalpy—that is, binding increases the stability of the CDR to listeriosis, ehrlichiosis, leishmaniasis, brucellosis, salmonellosis,
loops, especially CDR3. These results have led to the suggestion mumps meningitis, malaria, and toxoplasmosis.
that initial binding focuses on the interaction between CDRs 1
and 2 and the MHC. After this initial recognition, the CDR3s Superantigens
change their shape to maximize the area of contact. Conforma- SAgs are a special class of TCR ligands that have the ability
tional flexibility, or “induced fit,” would allow TCRs to rapidly to activate large fractions (5–20%) of the T-cell population.
sample many similar pMHC complexes, stopping only when Activation requires simultaneous interaction between the SAg,
their CDR3s are able to stabilize the interaction. the TCR Vβ domain, and a MHC class II molecule on the surface
of an APC. 23
TCR Binding Affinity Unlike conventional antigens, SAgs do not require processing
The affinity with which the TCR ultimately binds its ligand is a to allow them to bind class II molecules or activate T cells. Instead
critical determinant of T-cell activation. It is, however, only one of binding to the peptide antigen-binding groove, SAgs interact
factor in determining the overall avidity of the interaction, since with polymorphic residues on the periphery of the class II
other cell surface molecules of the T cell (e.g., CD4, CD8, CD2, molecule. Rather than binding to TCR β CDR3 residues, SAg
and various integrins) bind to cell surface molecules on the can interact with polymorphic residues in CDR1, CDR2, and
antigen-bearing cell to stabilize cell–cell TCR–ligand interactions. HV4. Soluble TCR β chains can also bind the appropriate SAg
Furthermore, since both the TCR and the pMHC ligand are in the absence of a TCR α chain. As a consequence, although
surface membrane proteins, each T cell can provide multiple the SAg links the TCR to the MHC, the T-cell responses are not
TCRs in the same plane that can bind multiple pMHC molecules “MHC restricted” in the conventional sense, since a T cell with
on the surface of the APC. This makes binding of TCR to pMHC the appropriate Vβ will respond to a SAg bound to a variety of
functionally multivalent, enhancing the apparent affinity of the polymorphic class II molecules.
interaction.
Atypical Antigens IMMUNOGLOBULIN GENE ORGANIZATION
Some αβ T cells can recognize lipid antigens when they are Each of the component chains of Igs and TCRs is encoded by
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complexed with members of the CD1 family. The interac- a separate multigene family. 24,25 The paradox of variability in
tion of TCR αβ with CD1 resembles that of TCR αβ with the V region in conjunction with a nearly invariable constant
MHC class I. Allelic polymorphism in CD1 is limited, which region was resolved when it was shown that Ig V and C domains
theoretically would restrict the range of lipid antigens that can are encoded by independent elements, or gene segments, within
be bound. each gene family. As a result, several gene elements are used to