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of di¨erentiated function such as cytotoxic activity and production of cytokines
(Cantrell, 1996).
THE T-CELL RECEPTOR
Rearrangement, Diversity, and Genetics
TCRs are highly polymorphic. The generation of primary sequence diversity in
mature TCR genes results from a nonconservative somatic recombination pro-
cess taking place between interspersed variable ( V ), diversity (D), and joining
(J ) TCR gene segments ( Davis and Bjorkman, 1988). This process is highly
analogous to that involved in the generation of antibody diversity (Tonegawa,
1983). Recombination is initiated at speci®c sites termed recombination signal
sequences (RSS), which ¯ank the gene segments to be rearranged and are
speci®cally targeted by the RAG1±RAG2 recombinase ( Ramsden et al., 1997;
Schatz et al., 1989; van Gent et al., 1996). During this process, coding ends are
di¨erentially processed by exonuclease and terminal deoxynucleotidyl trans-
ferase, leading to the generation of tremendous primary DNA sequence diver-
sity at the V( D)J interface (Gil®llan et al., 1993; Komori et al., 1993). Coding
and signal joints are then relegated while intervening stretches of DNA are lost
( Lewis, 1994). TCR rearrangement occurs during thymocyte maturation. Func-
tional rearrangement of the TCR b chain prevents recombination of the second
b chain allele, which often remains in germ-line con®guration. a Chain re-
arrangement then proceeds, but allelic exclusion is weaker than with the b chain
(Malissen et al., 1988, 1992). Hence, a proportion (> 30%) of peripheral T cells
expresses two functional TCR a chains, but the physiological signi®cance of
this phenomenon is unclear.
Over the years, at least 47 di¨erent functionally expressed TCR b chain
variable region ( TCRBV ) genes and a large number of alleles were described,
largely based on studies of cDNA and genomic libraries (reviewed in Arden
et al., 1995; Wei et al., 1994). These genes were grouped into 34 families and
a number of subfamilies based on nucleotide sequence relatedness, laying the
foundation for the TCR b chain gene nomenclature currently in use ( WHO-
IUIS, 1995). Two functional TCRBD, 13 TCRBJ, 42 TCRAV, and over 60
di¨erent TCRAJ gene segments were similarly described (Arden et al., 1995;
Yoshikai et al., 1985). The majority of TCR V-region genes show a large degree
of allelic polymorphism, resulting in a very large number of TCR V-region
haplotypes segregating within the general population (Cornelis et al., 1993;
Posnett et al., 1986). The TCR b chain locus occupies 685 kb of DNA on
human chromosome 7, where it comprises eight modular blocks of divergent
homology units encoding ordered assemblies of TCRBV genes (Rowen et al.,
1996). This suggests that the TCR loci have evolved through replicative dupli-
cation of an ancestral prototypic V gene subunit. Indeed, the b chain locus is
rich in repetitive DNA derived from various classes of transposable elements,
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