Biology Reference
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counterparts, possibly because TCR a chain V-region determinants are some-
what less immunogenic. In the majority of cases, epitopes recognized by V-
speci®c mAbs have not been precisely mapped. However, the important issues
of V-gene speci®city, cross-reactivity, and correspondence with ancient and
current TCRBV nomenclatures have been addressed in a recent workshop
(Posnett et al., 1996). For all these reasons, ¯ow cytometric analysis has be-
come the ``gold standard'' for studying TCR repertoire variations.
When combined with other techniques of clonal analysis, TCR repertoire
typing by ¯ow cytometry can yield a detailed picture of the kinetics, diversity,
and persistence of T-cell responses during the course of a pathogenic process.
As a prime example, alterations in the TCR b chain repertoire observed in
various mice strains were linked to infection with mouse mammary tumor viruses
(MMTV ) expressing viral superantigens (SAgs), or to the endogenous presence
of these MMTVs as germ-line integrants (Dyson et al., 1991; Frankel et al.,
1991; Marrack et al., 1991; Woodland et al., 1991). SAgs are thought to form a
bridge between MHC class II molecules and the TCR, leading to the activation
of large subsets of T cells expressing speci®c TCRBV families (Lavoie et al.,
1999). This is because the TCR b chain and, in particular, the CDR4 segment,
were found to be the central determinants of T-cell reactivity to bacterial and
viral SAgs ( Pullen et al., 1990, 1991; Reinherz et al., 1999). MMTV SAgs were
shown to play a critical role in the viral life cycle and in host-pathogen inter-
actions (Golovkina et al., 1992; Held et al., 1996). Since these discoveries, TCR
repertoire analysis has been used with varying success as an indirect attempt to
reveal the presence of putative SAgs in a number of animal and human path-
ologies. Among others, these include rheumatoid arthritis ( Paliard et al., 1991),
multiple sclerosis ( Utz et al., 1993), toxic shock syndrome (Scholl et al., 1989),
as well as infection with rabies virus ( Lafon et al., 1992), Epstein-Barr virus
(EBV ) (Smith et al., 1993), cytomegalovirus (CMV ) (Dobrescu et al., 1995,
1995b), and human immunode®ciency virus type 1 (HIV-1).
TCR REPERTOIRE ANALYSIS IN HIV-ASSOCIATED DISEASE
The Superantigen Hypothesis
Because acquired immunode®ciency syndrome (AIDS) is caused by a retro-
virus, a perfectly reasonable parallel was drawn with MMTV infection, ac-
cording to which the progressive depletion of CD4 T cells observed in HIV
disease could be linked to sequential activation and deletion of CD4 T-cell
subsets by a polymorphic, HIV-associated SAg (Janeway, 1991). It was soon
reported that TCRBV-speci®c deletions of T-cell subsets and various other
perturbations of the TCR repertoire could indeed be readily observed in HIV-
infected patients (Boldt-Houle et al., 1993; Dalgleish et al., 1992; De Paoli et
al., 1993; Hodara et al., 1993; Imberti et al., 1991). Overall, perturbations re-
ported were inconsistent, did not involve preferential deletion of CD4 T-cell
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