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A Single D_H Gene Segment Creates Its Own Unique CDR-H3 Repertoire and Is Sufficient for B cell Development and Immune Function¹

Robert L. Schelonka^2,*, Ivaylo I. Ivanov^2,3,*, David H. Jung, Gregory C. Ippolito^*, Lars Nitschke, Yingxin Zhuang^*, G. Larry Gartland^*, Jukka Pelkonen, Frederick W. Alt, Klaus Rajewsky and Harry W. Schroeder, Jr^4,*,

^* Departments of Pediatrics, Microbiology, Medicine, and Genetics, University of Alabama, Birmingham, AL 35294; The Center for Blood Research, Harvard Medical School, Boston, MA 02115; Department of Genetics, Universität Erlangen-Nürnberg, Erlangen, Germany; and Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland

To test the contribution of individual D gene segments to B cell development and function, we used gene targeting to create mice that contain only DFL16.1 in the D_H locus. We term this D-limited IgH allele D-DFL. Although the absolute number of IgM⁺IgD^– B cells in the bone marrow was decreased, homozygous D-DFL BALB/c mice contained normal numbers of IgM⁺IgD⁺ B cells in bone marrow and spleen and normal numbers of B1a, B1b, and B2 cells in the peritoneal cavity. Bone marrow IgM⁺IgD⁺ B cells express a CDR-H3 repertoire similar in length and amino acid composition to the DFL16.1 subset of the wild-type BALB/c repertoire but divergent from sequences that do not contain DFL16.1. This similarity in content is the product of both germline bias and somatic selection, especially in the transition to the mature IgM⁺IgD⁺ stage of development. Serum Ig concentrations and the humoral immune response to a T-dependent Ag ([4-hydroxy-3-nitrophenyl]acetyl hapten) were nearly identical to wild-type littermate controls. A greater variance in the immune response to the T-independent Ag ((13)-dextran) was observed in D-DFL homozygotes, with half of the mice exhibiting levels below the range exhibited by controls. Although limited to a repertoire specific to DFL16.1, the presence of a single D_H gene segment of normal sequence was sufficient for development of normal numbers of mature B cells and for robust humoral immune function.

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