Regulation of the TCRα repertoire by the survival window of CD4+CD8+ thymocytes

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T cell receptor (TCR) α alleles undergo primary and secondary rearrangement in double-positive (DP) thymocytes. By analyzing TCRα rearrangement in orphan nuclear receptor RORγ-deficient mice, in which the DP lifespan is shorter, and in Bcl-xL–transgenic mice, in which the DP lifespan is extended, we show that the progression of secondary Vα to Jα rearrangements is controlled by DP thymocyte survival. In addition, because Bcl-xL induces a bias towards 3′ Jα usage in peripheral T cells, we conclude that the programmed cell death of DP thymocytes is not simply a consequence of failed positive selection. Rather, it limits the progression of rearrangement along the Jα locus and the opportunities for positive selection, thereby regulating the TCRα repertoire.

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Figure 1: RORγ and/or RORγt promote thymocyte differentiation from the ISP to the DP stage.
Figure 2: Impaired 3′ Jα usage in RORγ−/− mice.
Figure 3: Impaired 3′ Jα usage in RORγ−/− mice is due to defective Vα to Jα recombination.
Figure 4: Histone H3 acetylation status of 3′ Jα chromatin.
Figure 5: Bcl-xL expression in DP thymocytes promotes 3′ Jα usage in thymus.
Figure 6: Bcl-xL expression in DP thymocytes promotes 3′ Jα usage in splenocytes.
Figure 7: Impaired 5′ Vα usage in RORγ−/− mice.


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We thank H. Yin for help with Southern blot analysis; M. Cook in the Flow Cytometry Facility of DUMC for help on cell sorting; and W. O'Brien and M. J. Sunshine for help with the mouse breeding and typing. Supported by grant RSG-0125201 from the American Cancer Society (to Y.-W. H.) and NIH grants GM41052 (to M. S. K.) and AI33856 (to D. R. L.).

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Correspondence to You-Wen He.

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