A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation

Rebecca Mathew, Ai Ping Mao, Andrew H. Chiang, Clara Bertozzi-Villa, Jeffrey J. Bunker, Seth T. Scanlon, Benjamin D. McDonald, Michael G. Constantinides, Kristin Hollister, Jeffrey D. Singer, Alexander Dent, Aaron R. Dinner, Albert Bendelac

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Induction of Bcl6 (B cell lymphoma 6) is essential for T follicular helper (Tfh) cell differentiation of antigen-stimulated CD4+ T cells. Intriguingly, we found that Bcl6 was also highly and transiently expressed during the CD4+CD8+ (double positive [DP]) stage of T cell development, in association with the E3 ligase cullin 3 (Cul3), a novel binding partner of Bcl6 which ubiquitinates histone proteins. DP stage-specific deletion of the E3 ligase Cul3, or of Bcl6, induced the derepression of the Bcl6 target genes Batf (basic leucine zipper transcription factor, ATF-like) and Bcl6, in part through epigenetic modifications of CD4+ single-positive thymocytes. Although they maintained an apparently normal phenotype after emigration, they expressed increased amounts of Batf and Bcl6 at basal state and produced explosive and prolonged Tfh responses upon subsequent antigen encounter. Ablation of Cul3 in mature CD4+ splenocytes also resulted in dramatically exaggerated Tfh responses. Thus, although previous studies have emphasized the essential role of Bcl6 in inducing Tfh responses, our findings reveal that Bcl6-Cul3 complexes also provide essential negative feedback regulation during both thymocyte development and T cell activation to restrain excessive Tfh responses.

Original languageEnglish
Pages (from-to)1137-1151
Number of pages15
JournalJournal of Experimental Medicine
Volume211
Issue number6
DOIs
StatePublished - 2014

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Cullin Proteins
B-Cell Lymphoma
Cell Differentiation
Ubiquitin-Protein Ligases
Thymocytes
T-Lymphocytes
Basic-Leucine Zipper Transcription Factors
Differentiation Antigens
Emigration and Immigration
Epigenomics
Histones

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Mathew, R., Mao, A. P., Chiang, A. H., Bertozzi-Villa, C., Bunker, J. J., Scanlon, S. T., ... Bendelac, A. (2014). A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation. Journal of Experimental Medicine, 211(6), 1137-1151. https://doi.org/10.1084/jem.20132267

A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation. / Mathew, Rebecca; Mao, Ai Ping; Chiang, Andrew H.; Bertozzi-Villa, Clara; Bunker, Jeffrey J.; Scanlon, Seth T.; McDonald, Benjamin D.; Constantinides, Michael G.; Hollister, Kristin; Singer, Jeffrey D.; Dent, Alexander; Dinner, Aaron R.; Bendelac, Albert.

In: Journal of Experimental Medicine, Vol. 211, No. 6, 2014, p. 1137-1151.

Research output: Contribution to journalArticle

Mathew, R, Mao, AP, Chiang, AH, Bertozzi-Villa, C, Bunker, JJ, Scanlon, ST, McDonald, BD, Constantinides, MG, Hollister, K, Singer, JD, Dent, A, Dinner, AR & Bendelac, A 2014, 'A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation', Journal of Experimental Medicine, vol. 211, no. 6, pp. 1137-1151. https://doi.org/10.1084/jem.20132267
Mathew, Rebecca ; Mao, Ai Ping ; Chiang, Andrew H. ; Bertozzi-Villa, Clara ; Bunker, Jeffrey J. ; Scanlon, Seth T. ; McDonald, Benjamin D. ; Constantinides, Michael G. ; Hollister, Kristin ; Singer, Jeffrey D. ; Dent, Alexander ; Dinner, Aaron R. ; Bendelac, Albert. / A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 6. pp. 1137-1151.
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