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which could confer a degree of genetic ¯exibility consistent with the diversity
and polymorphism of the b chain locus (Smit and Riggs, 1996).
Structure and Function
TCR components are members of the immunoglobulin ( Ig) gene superfamily.
As with Igs, alignment of TCR genes reveals ``framework'' regions of relative
homology interspersed with three clusters of DNA sequence diversity (com-
plementarity-determining regions, CDR1, 2, and 3). The TCR b chain contains
a fourth variable segment (CDR4), located between CDR2 and CDR3. Early
models and functional mutagenesis data predicted that the CDRs were
exposed to solvent, forming a large hypervariable surface containing the site
involved in contacting the antigen-MHC complex (Chothia, 1988; Jorgensen
et al., 1992; White et al., 1993). Since then, this representation was largely
con®rmed by X-ray crystallography (Bentley et al., 1995; Fields et al., 1995;
Garboczi et al., 1996; Garcia et al., 1998; Reinherz et al., 1999). CDR3 is the
most polymorphic TCR domain and the one most directly involved with anti-
genic peptide recognition. Three key structural features of CDR3 predomi-
nantly contribute to this interaction: a) the amino-acid sequence of CDR3,
which is critical for physical recognition of the antigenic peptide; b) CDR3
length, which in¯uences how deep the loop can reach into the peptide-binding
groove of the MHC molecule and represents the ®rst structural feature to be
®xed during the maturation of antigen-speci®c immune responses (McHeyzer-
Williams and Davis, 1995; Rock et al., 1994); and c) the identity of the J seg-
ment used in TCR rearrangement, inasmuch as germ-line J region contributes
at least four polymorphic residues to the C-terminal portion of CDR3. As will
be discussed below, the study of some of these structural features has revealed
important characteristics of antigen-speci®c T cell-mediated immune responses.
The TCR Repertoire
As a general rule, each individual T-cell clone bears a unique cell-surface TCR
a=b combination, corresponding to a de®ned antigenic speci®city. The TCR
repertoire is operationally de®ned as the sum of all TCR combinations and
speci®cities expressed by peripheral T cells within a given host. The extent of
TCR diversity that can be generated through the rearrangement process is
astonishing: over 10 15 di¨erent TCRs and combinations can be produced, suf-
®cient in theory to enable the recognition of every conceivable peptide antigen
(Davis and Bjorkman, 1988). The TCR repertoire is shaped during positive and
negative thymic selection. That, as well as a number of molecular constraints,
imposes practical limitations on the size and variability of the ``mature'' peri-
pheral TCR repertoire (Arstila et al., 1999). In the absence of pathology, the
TCR repertoire is fairly stable through time within individual subjects (Malth-
ora et al., 1992). Therefore, it can act as a low-resolution molecular ``®nger-
print'' of the cell-mediated branch of an individual's immune system, and be
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