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Regulation of T cell receptor α gene assembly by a complex hierarchy of germline Jα promoters

Abstract

Assembly of the gene encoding T cell receptor α (Tcra) is characterized by an orderly progression of primary and secondary Vα-to-Jα recombination events across the Jα array, but the targeting mechanisms responsible for this progression are mostly unknown. Studies have shown that the T early-α promoter is important in targeting primary Tcra rearrangements. We found that T early-α and a previously unknown promoter associated with Jα49 targeted primary recombination to discrete sets of constant α region (Cα)–distal Jα segments and together directed nearly all normal primary recombination events. Furthermore, deletion of the T early-α promoter activated previously suppressed downstream promoters and stimulated primary rearrangement to centrally located Jα segments. Central promoter derepression also occurred after primary rearrangement, thereby providing a mechanism to target secondary recombination events.

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Figure 1: A promoter upstream of Jα49.
Figure 2: Generation of mice with TEA and Jα49 promoter deletion.
Figure 3: Primary Jα usage in mice with TEA and Jα49 promoter deletion.
Figure 4: Jα repertoires of mice with TEA and Jα49 promoter deletion.
Figure 5: Quantitative Southern blot analysis of Jα rearrangement on a ΔTEAΔJ49 allele.
Figure 6: Jα array histone modifications in mice with TEA and Jα49 promoter deletion.
Figure 7: Germline JαCα transcription in mice with TEA and Jα49 promoter deletion.

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Acknowledgements

We thank E. Oltz (Vanderbilt University, Nashville, Tennessee), B. Sleckman (Washington University, St. Louis, Missouri), Y. Zhuang and I. Abarrategui for critical review of the manuscript. Supported by the National Institutes of Health (GM41052 to M.S.K.).

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Correspondence to Michael S Krangel.

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Supplementary information

Supplementary Table 1

Primers used for Jα repertoire analysis (PDF 55 kb)

Supplementary Table 2

Primers used for chromatin immunoprecipitation analysis (PDF 42 kb)

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Hawwari, A., Bock, C. & Krangel, M. Regulation of T cell receptor α gene assembly by a complex hierarchy of germline Jα promoters. Nat Immunol 6, 481–489 (2005). https://doi.org/10.1038/ni1189

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