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V_H Gene Replacement in Thymocytes¹

Rachel Golub^2,*, Denise Martin^*, Fred E. Bertrand, Marilia Cascalho, Matthias Wabl and Gillian E. Wu^*

^* Department of Immunology and Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada; University of Minnesota Cancer Center, Minneapolis, MN 55455; and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143

The quasi-monoclonal (QM) mouse has a functionally rearranged H chain gene inserted into its natural position in the IgH locus. In this position, the H chain gene is subject to many of the same activities as normally arranged H chain genes, including somatic hypermutation, V_H gene replacement, and class switch recombination. Here, we have used this mouse strain to determine some of the rules that govern the V(D)J recombination activity of the IgH locus in thymus. We focused on the requirements for V_H gene replacement. In normal mice, thymic DJ_H rearrangements are common, but VDJ_H rearrangements are not. We found intermediate products of V_H replacement in double-positive CD4⁺CD8⁺ cells of the QM thymus, demonstrating that the inserted V_H gene was accessible and ruling out the possibility that a V_H gene per se cannot be rearranged in the thymus. We found transcripts from the knocked-in H chain gene of QM, but no µ H chain protein was detectable in thymocytes. Cloning and sequencing of these transcripts revealed that some had been generated by V_H gene replacement. Corresponding signal joints could also be identified. These results suggest that neither a B cell-specific signal nor an Ig protein are necessary to activate V_H-to-VDJ_H joining in thymocytes. Possible mechanisms remaining to account for overcoming the barrier to V_H joining in thymocytes include the insertion of a transcriptionally active gene segment and/or the inactivation of a silencer.

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