BCL6 is critical for the development of a diverse primary B cell repertoire

Cihangir Duy, J. Jessica Yu, Rahul Nahar, Srividya Swaminathan, Soo Mi Kweon, Jose M. Polo, Ester Valls, Lars Klemm, Seyedmehdi Shojaee, Leandro Cerchietti, Wolfgang Schuh, Hans Martin Jäck, Christian Hurtz, Parham Ramezani-Rad, Sebastian Herzog, Hassan Jumaa, H. Phillip Koeffler, Ignacio Moreno De Alborán, Ari M. Melnick, B. Hilda YeMarkus Müschen

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Rα-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.

Original languageEnglish (US)
Pages (from-to)1209-1221
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number6
DOIs
StatePublished - Jun 7 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Duy, C., Yu, J. J., Nahar, R., Swaminathan, S., Kweon, S. M., Polo, J. M., Valls, E., Klemm, L., Shojaee, S., Cerchietti, L., Schuh, W., Jäck, H. M., Hurtz, C., Ramezani-Rad, P., Herzog, S., Jumaa, H., Koeffler, H. P., De Alborán, I. M., Melnick, A. M., ... Müschen, M. (2010). BCL6 is critical for the development of a diverse primary B cell repertoire. Journal of Experimental Medicine, 207(6), 1209-1221. https://doi.org/10.1084/jem.20091299