Regulation of T cell receptor β allelic exclusion at a level beyond accessibility

Annette Jackson; Hrisavgi D. Kondilis; Bernard Khor; Barry P. Sleckman; Michael S. Krangel

doi:10.1038/ni1157

Regulation of T cell receptor β allelic exclusion at a level beyond accessibility

Annette Jackson, Hrisavgi D. Kondilis, Bernard Khor, Barry P. Sleckman, Michael S. Krangel

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

Allelic exclusion of V_β-to-DJ_β recombination depends on asynchronous rearrangement of alleles of the gene encoding T cell receptor β in double-negative thymocytes and feedback inhibition that is maintained in double-positive thymocytes. Feedback is thought to be enforced through downregulation of V_β accessibility. In an attempt to override this negative regulation, we introduced the enhancer of the gene encoding T cell receptor α into the V_β gene cluster downstream of V_β12. In double-negative thymocytes, the introduced enhancer had no measurable effect on accessibility, but V_β12 rearrangement was stimulated and V_β12 allelic exclusion was partially subverted. In contrast, double-positive thymocytes showed increased V_β transcription and accessibility, but feedback inhibition of V_β-to-DJ_β recombination remained intact. Our results indicate additional regulatory constraints on V_β-to-DJ_β recombination that operate beyond the accessibility barrier.

Original language	English (US)
Pages (from-to)	189-197
Number of pages	9
Journal	Nature Immunology
Volume	6
Issue number	2
DOIs	https://doi.org/10.1038/ni1157
State	Published - Feb 2005
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni1157

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title = "Regulation of T cell receptor β allelic exclusion at a level beyond accessibility",

abstract = "Allelic exclusion of Vβ-to-DJβ recombination depends on asynchronous rearrangement of alleles of the gene encoding T cell receptor β in double-negative thymocytes and feedback inhibition that is maintained in double-positive thymocytes. Feedback is thought to be enforced through downregulation of Vβ accessibility. In an attempt to override this negative regulation, we introduced the enhancer of the gene encoding T cell receptor α into the Vβ gene cluster downstream of Vβ12. In double-negative thymocytes, the introduced enhancer had no measurable effect on accessibility, but Vβ12 rearrangement was stimulated and Vβ12 allelic exclusion was partially subverted. In contrast, double-positive thymocytes showed increased Vβ transcription and accessibility, but feedback inhibition of Vβ-to-DJβ recombination remained intact. Our results indicate additional regulatory constraints on Vβ-to-DJβ recombination that operate beyond the accessibility barrier.",

author = "Annette Jackson and Kondilis, {Hrisavgi D.} and Bernard Khor and Sleckman, {Barry P.} and Krangel, {Michael S.}",

note = "Funding Information: We thank L. Martinek of the Duke University Cancer Center Flow Cytometry Facility for help with cell sorting and analysis; T. Wehrly and H. Boutrid for technical assistance; and Y. Zhuang, Y.-W. He and G. Kelsoe for critical review of the manuscript. Supported by the National Institutes of Health (AI49934 to M.S.K. and NIAID-T32 AI052077 to H.D.K.) and National Science Foundation (A.J.).",

year = "2005",

month = feb,

doi = "10.1038/ni1157",

language = "English (US)",

volume = "6",

pages = "189--197",

journal = "Nature Immunology",

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publisher = "Nature Publishing Group",

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T1 - Regulation of T cell receptor β allelic exclusion at a level beyond accessibility

AU - Jackson, Annette

AU - Kondilis, Hrisavgi D.

AU - Khor, Bernard

AU - Sleckman, Barry P.

AU - Krangel, Michael S.

N1 - Funding Information: We thank L. Martinek of the Duke University Cancer Center Flow Cytometry Facility for help with cell sorting and analysis; T. Wehrly and H. Boutrid for technical assistance; and Y. Zhuang, Y.-W. He and G. Kelsoe for critical review of the manuscript. Supported by the National Institutes of Health (AI49934 to M.S.K. and NIAID-T32 AI052077 to H.D.K.) and National Science Foundation (A.J.).

PY - 2005/2

Y1 - 2005/2

N2 - Allelic exclusion of Vβ-to-DJβ recombination depends on asynchronous rearrangement of alleles of the gene encoding T cell receptor β in double-negative thymocytes and feedback inhibition that is maintained in double-positive thymocytes. Feedback is thought to be enforced through downregulation of Vβ accessibility. In an attempt to override this negative regulation, we introduced the enhancer of the gene encoding T cell receptor α into the Vβ gene cluster downstream of Vβ12. In double-negative thymocytes, the introduced enhancer had no measurable effect on accessibility, but Vβ12 rearrangement was stimulated and Vβ12 allelic exclusion was partially subverted. In contrast, double-positive thymocytes showed increased Vβ transcription and accessibility, but feedback inhibition of Vβ-to-DJβ recombination remained intact. Our results indicate additional regulatory constraints on Vβ-to-DJβ recombination that operate beyond the accessibility barrier.

AB - Allelic exclusion of Vβ-to-DJβ recombination depends on asynchronous rearrangement of alleles of the gene encoding T cell receptor β in double-negative thymocytes and feedback inhibition that is maintained in double-positive thymocytes. Feedback is thought to be enforced through downregulation of Vβ accessibility. In an attempt to override this negative regulation, we introduced the enhancer of the gene encoding T cell receptor α into the Vβ gene cluster downstream of Vβ12. In double-negative thymocytes, the introduced enhancer had no measurable effect on accessibility, but Vβ12 rearrangement was stimulated and Vβ12 allelic exclusion was partially subverted. In contrast, double-positive thymocytes showed increased Vβ transcription and accessibility, but feedback inhibition of Vβ-to-DJβ recombination remained intact. Our results indicate additional regulatory constraints on Vβ-to-DJβ recombination that operate beyond the accessibility barrier.

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Regulation of T cell receptor β allelic exclusion at a level beyond accessibility

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