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Analysis of an Ethylnitrosourea-generated Mouse Mutation Defines a Cell Intrinsic Role of Nuclear Factor B2 in Regulating Circulating B Cell Numbers

Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia

Address correspondence to Christopher C. Goodnow, Australian Cancer Research Foundation Genetics Laboratory, Medical Genome Centre, John Curtin School of Medical Research, Mills Rd., PO Box 334, Australian National University, Canberra ACT 2601, Australia. Phone: 61-2-6125-3621; Fax: 61-2-6125-8512; E-mail: Chris.Goodnow{at}anu.edu.au

The number of circulating follicular B lymphocytes is normally kept within a precise range despite their dispersion through the body and daily overproduction of precursors in the bone marrow. By establishing a genome wide recessive mutation screen in C57BL/6 mice to identify critical components of immune system regulation, we identified a mutant strain with selective deficiency in recirculating B cells but not immature or peritoneal B1 cells. Analysis of mixed bone marrow chimeras established that the mutation affects a cell autonomous process within B cells that is required for their accumulation after emigrating to peripheral lymphoid organs. The defect is caused by a point mutation in the gene encoding transcription factor nuclear factor (NF)-B2, terminating the encoded protein within the DNA-binding domain. These findings establish the feasibility of analyzing immune regulation by genome wide mutant screens and demonstrates an intrinsic requirement for NF-B2 in regulating circulating follicular B cell numbers.

Key Words: Rel/NF-B • B lymphocytes • follicular • ethylnitrosourea • mutagenesis

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