LIMITATIONS IN PLASTICITY OF THE T-CELL RECEPTOR REPERTOIRE

How constrained is T-cell recognition? Is a truncated T-cell receptor (TCR) repertoire, missing half of its V-beta-components (where V indicates variable), still broad enough to produce an antigen-specific T-cell response to all determinants? These questions can be answered for certain T-cell antigenic determinants whose response in the wild type is limited to specific gene segments. Our results show that mice with such a deletion in their TCR V-beta-genes (V-beta truncated haplotype, V-beta-a) are unable to respond to two antigen determinants (sperm whale myoglobin 111-121/I-E(d) and myelin basic protein 1-11/I-A(u)) whose response in the wild type is restricted to the missing V-beta (V-beta-8.2 in the case of 111-121/I-E(d) and V-beta-8.2 and V-beta-13 in the case of 1-11/I-A(u)) gene segments. Fundamentally, this restriction could have been attributed to another aspect of immunodominance-that a favored TCR with high affinity would dominate the response, but in its absence, a hierarchy of T cells with lesser efficiency and expressing alternate TCR V genes could take over. However, from our experiments it has become evident that there is an absolute limit to the flexibility inherent in the TCR repertoire. Since it is clear that mouse populations have many ambient deletion ligands (such as self-superantigens) that can result in the loss of multiple V-beta-gene segments during normal T-cell development, these deletions can have serious consequences, such as unresponsiveness to the antigen as a whole-a hole in the repertoire-if a dominant determinant of that antigen normally shows restricted TCR V-beta-gene usage.