T-CELL RECEPTOR GENE RECOMBINATION PATTERNS AND MECHANISMS - CELL-DEATH, RESCUE, AND T-CELL PRODUCTION

The antigen-specific receptors of T and B lymphocytes are generated by somatic recombination between noncontiguous gene segments encoding th e variable portions of these molecules. The semirandom nature of this process, while desirable for the generation of diversity, has been tho ught to exact a high price in terms of sterile (out-of-frame) products . Historically, the majority of T lymphocytes generated in mammals wer e thought to be useless, either because they generated such sterile re arrangements or because the receptors generated did not appropriately recognize self-molecules (i.e., positive and negative selection). In t he studies described here, we characterize the onset of T cell recepto r (TCR) alpha and beta chain gene rearrangements and quantitate their progression throughout T cell development. The results show that T cel l production efficiency is enhanced through (a) rearrangement of TCR-b eta chain genes early during T cell development, with selective expans ion of those cells possessing in-frame rearrangements; (b) deletion of sterile rearrangements at the TCR-alpha chain locus through ordered ( proximal to distal) sequential recombination; and (c) modification of nonselectable alpha/beta heterodimer specificities through generation and expression of new TCR-alpha chains. In addition, we demonstrate st rict correlations between successful TCR-beta gene rearrangement, the onset of TCR-alpha gene rearrangement, rapid cell division, and progra mmed cell death, which together serve to maintain cell turnover and ho meostasis during T cell development.