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Underutilization of the V10C Gene in the B Cell Repertoire Is Due to the Loss of Productive VJ Rearrangements During B Cell Development

Sean P. Fitzsimmons^1,*, Kathleen J. Clark^*, Howard S. Mostowski and Marjorie A. Shapiro^1,*

^* Division of Monoclonal Antibodies and Division of Cellular and Gene Therapies, Food and Drug Administration, Center for Biologics Evaluation and Research, Rockville, MD 20852

The V10 family of murine light chain Ig genes is composed of three members, two of which (V10A and V10B) are well used. V10C, the third member of this family, is not detected in any expressed Abs. Our previous work showed that V10C is structurally functional and can recombine, but mRNA levels in spleen were extremely low relative to those of V10A and V10B. Furthermore, while the V10C promoter was efficient in B cells, it was shown to work inefficiently in pre-B cell lines. Here, we extend our analysis of the V10 family and examine V10 gene accessibility, their representation in V cDNA phage libraries, and the frequency and nature of rearrangements during different stages of B cell development. We demonstrate that V10C is under-represented in V cDNA libraries, but that the frequency of its sterile transcripts in pre-B cells surpasses both V10A and V10B, indicating that the gene is as accessible as V10A and V10B to the recombination machinery. We also demonstrate that V10C recombines at a frequency equal to that of V10A in pre-B cells and has a normal nonproductive to productive recombination ratio. As B cells develop, however, both the frequency of V10C rearrangements and the presence of productive rearrangements decline, indicating that these cells are in some fashion being eliminated.