T Cell Receptor (TCR)-β Gene Recombination: Dissociation from Cell Cycle Regulation and Developmental Progression During T Cell Ontogeny

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Abstract
T cell lymphopoiesis involves extensive cell division and differentiation; these must be balanced by export and programmed cell death to maintain thymic homeostasis. Details regarding the nature of these processes, as well as their relationships to each other and to the definitive process of T cell receptor (TCR) gene recombination, are presently emerging. Two widely held concepts are that cell cycle status is inherently and inversely linked to gene recombination and that the outcomes of gene recombination regulate developmental progression. In this study, we analyze TCR-β recombination and cell cycle status with respect to differentiation during early T cell ontogeny. We find that although differentiation, cell cycle fluctuations, and gene recombination are coincident during normal T cell development, differentiation and cell cycle status are not inherently linked to the recombination process or its products. Rather, recombination appears to occur in parallel with these events as part of a genetically patterned program of development. We propose that the outcome of gene recombination (i.e., TCR expression) may not influence developmental progression per se, but instead serves to perpetuate those developing cells that have been successful in recombination. The potential consequences of this model for the regulation of thymic lymphopoiesis and programmed cell death are discussed.