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Differential Transcriptional Regulation of Individual TCR V Segments Before Gene Rearrangement¹

Fei Chen^*, Lee Rowen, Lee Hood and Ellen V. Rothenberg^2,*

^* Division of Biology, California Institute of Technology, Pasadena, CA 91125; and Institute of Systems Biology, Seattle, WA 98105

The promoter sequences of individual murine TCR V segments are dissimilar, but any functional differences between them are masked after productive gene rearrangement by the dominance of the TCR 3' enhancer. However, thymocytes of recombination-activating gene-2 (Rag2)-deficient mice allow the transcriptional activity of V promoters to be studied before rearrangement. Here we report that many V segments are detectably transcribed in Rag2^-/- thymocytes and that there are significant differences in expression among different V segments. Primer extension and characterization of cDNA clones from SCID thymocytes suggest that these germline V transcripts generally use the same start sites as those previously determined in mature T cells. The strength of expression before rearrangement does not correlate with proximity to the known enhancer, because members of the most distal V cluster (V2.1, V1.1, V4.1) are relatively strongly expressed and more proximal V segments (V14.1, V3.1, V7.1, V6.1) are only weakly expressed. Different V segments also show different developmental programs of activation in different thymocyte subsets, with the V5.1(L)-8.2(V) spliced transcript expressed earliest as well as most strongly overall. Comparison with Rag⁺ MHC class I^-/- and class II^-/- thymocytes confirms that many of these expression differences are leveled by rearrangement and/or by selection, before MHC-dependent selection. However, the expression pattern of V2.1 is highly distinctive and includes cell types apparently outside the T lineage, suggesting potential acquisition of specialized roles.

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