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Ig Synthesis and Class Switching Do Not Require the Presence of the hs4 Enhancer in the 3' IgH Regulatory Region¹

Centre National de la Recherche Scientifique Unité Mixte de Recherche 6101, Université de Limoges, France

Several studies have reported that regulatory elements located 3' of the IgH locus (namely hs3a, hs1,2, hs3b, and hs4) might play a role during class switch recombination (CSR) and Ig synthesis. While individual deletion of hs3a or hs1,2 had no effect, pairwise deletion of hs3b (an inverted copy of hs3a) and hs4 markedly affected CSR and Ig expression. Among these two elements, hs4 was tentatively presented with the master role due to its unique status within the 3' regulatory region: distal position outside repeated regions, early activation in pre-B cells, strong activity throughout B cell ontogeny. To clarify its role, we generated mice with a clean deletion of the hs4 after replacement with a floxed neo^R cassette. Surprisingly, and as for previous deletion of hs3a or hs1,2, deletion of hs4 did not affect either in vivo CSR or the secretion level of any Ig isotype. In vitro CSR and Ig secretion in response to LPS and cytokines was not affected either. The only noticeable effects of the hs4 deletion were a decrease in the number of B splenocytes and a decreased membrane IgM expression. In conclusion, while dispensable for CSR and Ig transcription in plasma cells, hs4 mostly appears to contribute to Ig transcription in resting B lymphocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Ligue Contre le Cancer (Comité Départemental de la Haute-Vienne et de la Corrèze), Conseil Régional du Limousin, and "Lions Club de la Corrèze, Zone 33 District 103 Sud".

Y.D. and M.C. wrote the paper and performed and designed research. C.V.-F., V.T., R.F., and N.C. performed research.

² C.V.-F. and V.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Yves Denizot, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6101, Laboratoire d’Immunologie, 2, rue du Dr Marcland, 87025 Limoges Cedex, France. E-mail address: yves.denizot{at}unilim.fr

⁴ Abbreviations used in this paper: CSR, class switch recombination; ES, embryonic stem; LCR, locus control region; 3'RR, 3' regulatory region; wt, wild type.

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