Journal of Experimental Medicine, Vol 179, 43-55, Copyright © 1994 by Rockefeller University Press

ARTICLES

Enhancer-dependent and -independent steps in the rearrangement of a human T cell receptor delta transgene

P Lauzurica and MS Krangel
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710.

The rearrangement and expression of T cell receptor (TCR) gene segments occurs in a highly ordered fashion during thymic ontogeny of T lymphocytes. To study the regulation of gene rearrangement within the TCR alpha/delta locus, we generated transgenic mice that carry a germline human TCR delta minilocus that includes V delta 1, V delta 2, D delta 3, J delta 1, J delta 3, and C delta segments, and either contains or lacks the TCR delta enhancer. We found that the enhancer- positive construct rearranges stepwise, first V to D, and then V-D to J. Construct V-D rearrangement mimics a unique property of the endogenous TCR delta locus. V-D-J rearrangement is T cell specific, but is equivalent in alpha/beta and gamma/delta T lymphocytes. Thus, either there is no commitment to the alpha/beta and gamma/delta T cell lineages before TCR delta gene rearrangement, or if precommitment occurs, it does not operate directly on TCR delta gene cis-acting regulatory elements to control TCR delta gene rearrangement. Enhancer- negative mice display normal V to D rearrangement, but not V-D to J rearrangement. Thus, the V-D to J step is controlled by the enhancer, but the V to D step is controlled by separate elements. The enhancer apparently controls access to J delta 1 but not D delta 3, suggesting that a boundary between two independently regulated domains of the minilocus lies between these elements. Within the endogenous TCR alpha/delta locus, this boundary may represent the 5' end of a chromatin regulatory domain that is opened by the TCR delta enhancer during T cell development. The position of this boundary may explain the unique propensity of the TCR delta locus to undergo early V to D rearrangement. Our results indicate that the TCR delta enhancer performs a crucial targeting function to regulate TCR delta gene rearrangement during T cell development.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Chapiro, E., Delabesse, E., Asnafi, V., Millien, C., Davi, F., Nugent, E., Beldjord, K., Haferlach, T., Grimwade, D., Macintyre, E. A. (2006). Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia: implications for the cellular target of t(15;17). Blood 108: 3484-3493 [Abstract] [Full Text]  
• Olaru, A., Petrie, H. T., Livak, F. (2005). Beyond the 12/23 Rule of VDJ Recombination Independent of the Rag Proteins. J. Immunol. 174: 6220-6226 [Abstract] [Full Text]  
• Carabana, J., Ortigoza, E., Krangel, M. S. (2005). Regulation of the Murine D{delta}2 Promoter by Upstream Stimulatory Factor 1, Runx1, and c-Myb. J. Immunol. 174: 4144-4152 [Abstract] [Full Text]  
• Balmelle, N., Zamarreno, N., Krangel, M. S., Hernandez-Munain, C. (2004). Developmental Activation of the TCR {alpha} Enhancer Requires Functional Collaboration among Proteins Bound Inside and Outside the Core Enhancer. J. Immunol. 173: 5054-5063 [Abstract] [Full Text]  
• Asnafi, V., Radford-Weiss, I., Dastugue, N., Bayle, C., Leboeuf, D., Charrin, C., Garand, R., Lafage-Pochitaloff, M., Delabesse, E., Buzyn, A., Troussard, X., Macintyre, E. (2003). CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCR{gamma}{delta} lineage. Blood 102: 1000-1006 [Abstract] [Full Text]  
• Asnafi, V., Beldjord, K., Boulanger, E., Comba, B., Le Tutour, P., Estienne, M.-H., Davi, F., Landman-Parker, J., Quartier, P., Buzyn, A., Delabesse, E., Valensi, F., Macintyre, E. (2003). Analysis of TCR, pTalpha , and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. Blood 101: 2693-2703 [Abstract] [Full Text]  
• Bassing, C. H., Tillman, R. E., Woodman, B. B., Canty, D., Monroe, R. J., Sleckman, B. P., Alt, F. W. (2003). T cell receptor (TCR) alpha /delta locus enhancer identity and position are critical for the assembly of TCR delta and alpha variable region genes. Proc. Natl. Acad. Sci. USA 100: 2598-2603 [Abstract] [Full Text]  
• Hernandez-Munain, C., Krangel, M. S. (2002). Distinct Roles for c-Myb and Core Binding Factor/Polyoma Enhancer-Binding Protein 2 in the Assembly and Function of a Multiprotein Complex on the TCR {delta} Enhancer In Vivo. J. Immunol. 169: 4362-4369 [Abstract] [Full Text]  
• McMurry, M. T., Krangel, M. S. (2000). A Role for Histone Acetylation in the Developmental Regulation of V(D)J Recombination. Science 287: 495-498 [Abstract] [Full Text]  
• Zhong, X.-P., Carabana, J., Krangel, M. S. (1999). Flanking nuclear matrix attachment regions synergize with the T cell receptor delta enhancer to promote V(D)J recombination. Proc. Natl. Acad. Sci. USA 96: 11970-11975 [Abstract] [Full Text]  
• Zhong, X.-P., Krangel, M. S. (1999). Enhancer-Blocking Activity Within the DNase I Hypersensitive Site 2 to 6 Region Between the TCR {alpha} and Dad1 Genes. J. Immunol. 163: 295-300 [Abstract] [Full Text]  
• Riegert, P., Gilfillan, S. (1999). A Conserved Sequence Block in the Murine and Human TCR J{alpha} Region: Assessment of Regulatory Function In Vivo. J. Immunol. 162: 3471-3480 [Abstract] [Full Text]  
• NIKOLAJCZYK, B.S., DANG, W., SEN, R. (1999). Mechanisms of {micro} Enhancer Regulation in B Lymphocytes. Cold Spring Harb Symp Quant Biol 64: 99-108 [Abstract]  
• HERNANDEZ-MUNAIN, C., MCMURRY, M. T., KRANGEL, M.S. (1999). Regulation of Chromatin Accessibility for V(D)J Recombination. Cold Spring Harb Symp Quant Biol 64: 183-190 [Abstract]  
• Hempel, W. M., Stanhope-Baker, P., Mathieu, N., Huang, F., Schlissel, M. S., Ferrier, P. (1998). Enhancer control of V(D)J recombination at the TCRbeta locus: differential effects on DNA cleavage and joining. Genes Dev. 12: 2305-2317 [Abstract] [Full Text]  
• Kienker, L. J., Ghosh, M. R., Tucker, P. W. (1998). Regulatory Elements in the Promoter of a Murine TCRD V Gene Segment. J. Immunol. 161: 791-804 [Abstract] [Full Text]  
• Hernandez-Munain, C., Roberts, J. L., Krangel, M. S. (1998). Cooperation among Multiple Transcription Factors Is Required for Access to Minimal T-Cell Receptor alpha -Enhancer Chromatin In Vivo. Mol. Cell. Biol. 18: 3223-3233 [Abstract] [Full Text]  
• Livak, F., Schatz, D. G. (1998). Alternative splicing of rearranged T cell receptor delta  sequences to the constant region of the alpha  locus. Proc. Natl. Acad. Sci. USA 95: 5694-5699 [Abstract] [Full Text]  
• Kimura, N., Yoshida, T., Nagano, M., Tamura;, K., Suzuki, R., Seto, M., Morishima, Y., Nakamura, S. (1998). Importance of T-Cell Receptor delta -Chain Gene Analysis on CD7+ and CD56+ Myeloid/Natural Killer Cell Precursor Acute Leukemia. Blood 91: 2622-2624 [Full Text]  
• Zhong, X.-P., Krangel, M. S. (1997). An enhancer-blocking element between alpha  and delta  gene segments within the human T cell receptor alpha /delta  locus. Proc. Natl. Acad. Sci. USA 94: 5219-5224 [Abstract] [Full Text]  
• Lauzurica, P., Zhong, X.-P., Krangel, M. S., Roberts, J. L. (1997). Regulation of  T Cell Receptor delta  Gene Rearrangement by CBF/PEBP2. JEM 185: 1193-1202 [Abstract] [Full Text]  
• Roberts, J. L., Lauzurica, P., Krangel, M. S. (1997). Developmental Regulation of  VDJ Recombination By the Core Fragment of the T Cell Receptor alpha  Enhancer. JEM 185: 131-140 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS