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© The Rockefeller University Press, 0022-1007/1997/4/1193/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1193-1202

Article

Regulation of T Cell Receptor {delta} Gene Rearrangement by CBF/PEBP2

Pilar Lauzurica, Xiao-Ping Zhong, Michael S. Krangel, and Joseph L. Roberts

From the Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710

We have analyzed transgenic mice carrying versions of a human T cell receptor (TCR)-{delta} gene minilocus to study the developmental control of VDJ (variable/diversity/joining) recombination. Previous data indicated that a 1.4-kb DNA fragment carrying the TCR-{delta} enhancer (E{delta}) efficiently activates minilocus VDJ recombination in vivo. We tested whether the transcription factor CBF/PEBP2 plays an important role in the ability of E{delta} to activate VDJ recombination by analyzing VDJ recombination in mice carrying a minilocus in which the {delta}E3 element of E{delta} includes a mutated CBF/PEBP2 binding site. The enhancer-dependent VD to J step of minilocus rearrangement was dramatically inhibited in three of four transgenic lines, arguing that the binding of CBF/PEBP2 plays a role in modulating local accessibility to the VDJ recombinase in vivo. Because mutation of the {delta}E3 binding site for the transcription factor c-Myb had previously established a similar role for c-Myb, and because a 60-bp fragment of E{delta} carrying {delta}E3 and {delta}E4 binding sites for CBF/PEBP2, c-Myb, and GATA-3 displays significant enhancer activity in transient transfection experiments, we tested whether this fragment of E{delta} is sufficient to activate VDJ recombination in vivo. This fragment failed to efficiently activate the enhancerdependent VD to J step of minilocus rearrangement in all three transgenic lines examined, indicating that the binding of CBF/PEBP2 and c-Myb to their cognate sites within E{delta}, although necessary, is not sufficient for the activation of VDJ recombination by E{delta}. These results imply that CBF/PEBP2 and c-Myb collaborate with additional factors that bind elsewhere within E{delta} to modulate local accessibility to the VDJ recombinase in vivo.

Address correspondence to Dr. Michael S. Krangel, Department of Immunology, PO Box 3010, Duke University Medical Center, Durham, NC 27710. Dr. Lauzurica's present address is Seccion de Inmunologia, Hospital de la Princesa, 28006 Madrid, Spain.

1 Abbreviations used in this paper: D, diversity; J, joining; V, variable.


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