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Efficient Recombination of a Switch Substrate Retrovector in CD40-Activated B Lymphocytes: Implications for the Control of C_H Gene Switch Recombination¹

Jack Ballantyne^2,*, Diane L. Henry^2,*, Jurgen R. Muller^2,*, Francine Briere, Clifford M. Snapper, Marilyn Kehry^§ and Kenneth B. Marcu^3,*

^* Department of Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, State University of New York, Stony Brook, NY 11794; Laboratory for Immunological Research, Schering-Plough, Dardilly, France; Department of Pathology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and ^§ Department of Immunological Diseases, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877

Maturing B lymphocytes possess a recombination activity that switches the class of heavy chain Ig. The nature of the recombination activity, its molecular requirements and regulation remain elusive questions about B lymphocyte biology and development. Class switch recombination is controlled by cytokine response elements that are required to differentially activate C_H gene transcription before their subsequent recombination. Here, we show that cultures of purified murine and human B cells, stimulated only by CD40 receptor engagement, possess a potent switch recombination activity. CD40 ligand-stimulated murine and human B lymphocytes were infected with recombinant retroviruses containing Sµ and S2b sequences. Chromosomally integrated switch substrate retrovectors (SSRs), harboring constitutively transcribed S sequences, underwent extensive recombinations restricted to their S sequences with structural features akin to endogenous switching. SSR recombination commenced 4 days postinfection (5 days poststimulation) with extensive switch sequence recombination over the next 2 to 3 days. In contrast, endogenous S2b and S1 sequences did not undergo appreciable switch recombination upon CD40 signaling alone. As expected, IL-4 induced endogenous Sµ to S1 switching, while endogenous Sµ to S2b fusions remained undetectable. Surprisingly, IL-4 enhanced the onset of SSR recombination in CD40-stimulated murine B cells, with S-S products appearing only 2 days postinfection and reaching a maximum within 2 to 3 days. The efficiency of switch recombination with SSRs ressembles that seen for endogenous C_H class switching.

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