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Transcription of Ig Germline Genes in Single Human B Cells and the Role of Cytokines in Isotype Determination¹

David J. Fear^*,, Natalie McCloskey^*, Brian O’Connor, Gary Felsenfeld and Hannah J. Gould^2,*

^* The Randall Center, King’s College London, United Kingdom; Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Respiratory Medicine and Allergy, Guy’s, King’s, and St. Thomas’ School of Medicine, London, United Kingdom

We have developed a critical test of the chromatin accessibility model of Ig isotype determination in which local unfolding of chromatin higher order structure (chromatin accessibility) in the region of specific germline genes in the H chain locus determines the Ab class to be expressed in the B cell. We show that multiple germline genes are constitutively transcribed in the majority of naive human B cells in a population. Thus, because chromatin in its higher order structure cannot be transcribed, the entire Ig H chain locus must be unfolded in naive B cells. We have also established that IL-4 and anti-CD40 act by enhancing transcription in the majority of cells, rather than by activating transcription in more of the cells. Transcriptional activity in the human H chain locus rules out the perturbation of chromatin higher order structure as a factor in isotype determination. We have also found that the levels of germline gene transcription cannot fully account for the levels of secretion of the different Ig isotypes, and that secretion of IgE, in particular, is suppressed relative to that of IgG.

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