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Thymocyte Development: TCR Gene Rearrangements, Intracellular TCR Expression, and Developmental Potential—Differences between Men and Mice1,2
* Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
Department of Microbiology and Immunology and
Department of Surgery, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104
To evaluate the role of the TCR in the 
/
lineage choice during human thymocyte development, molecular analyses of the TCR locus in cells and the TCR and loci in cells were undertaken. TCR variable gene segments remained largely in germline configuration in cells, indicating that commitment to the lineage occurred before complete TCR rearrangements in most cases. The few TCR rearrangements detected were primarily out-of-frame, suggesting that productive TCR rearrangements diverted cells away from the lineage. In contrast, in cells, the TCR locus was almost completely rearranged with a random productivity profile; the TCR locus contained primarily nonproductive rearrangements. Productive rearrangements were, however, depleted compared with preselected cells. Productive TCR and rearrangements rarely occurred in the same cell, suggesting that cells developed from cells unable to produce a functional TCR. Intracellular TCR expression correlated with the up-regulation of CD4 and concomitant down-regulation of CD34, and plateaued at the early double positive stage. Surprisingly, however, some early double positive thymocytes retained potential in culture. We present a model for human thymopoiesis which includes development as a default pathway, an instructional role for the TCR in the / lineage choice, and a prolonged developmental window for selection and lineage commitment. Aspects that differ from the mouse are the status of TCR gene rearrangements at the nonexpressed loci, the timing of selection, and maintenance of potential through the early double positive stage of development.
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