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A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2014 Jun 02; Vol. 211 (6), pp. 1137-51. Date of Electronic Publication: 2014 May 26. - Publication Year :
- 2014
-
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.<br /> (© 2014 Mathew et al.)
- Subjects :
- Animals
Basic-Leucine Zipper Transcription Factors genetics
Basic-Leucine Zipper Transcription Factors immunology
Basic-Leucine Zipper Transcription Factors metabolism
Blotting, Western
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
Cell Differentiation genetics
Cullin Proteins genetics
Cullin Proteins metabolism
Feedback, Physiological
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Mice, Transgenic
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic genetics
Promoter Regions, Genetic immunology
Protein Binding immunology
Proto-Oncogene Proteins c-bcl-6 genetics
Proto-Oncogene Proteins c-bcl-6 metabolism
Receptors, Antigen, T-Cell genetics
Receptors, Antigen, T-Cell immunology
Receptors, Antigen, T-Cell metabolism
Reverse Transcriptase Polymerase Chain Reaction
Spleen cytology
Spleen immunology
Spleen metabolism
T-Lymphocytes, Helper-Inducer metabolism
Thymocytes immunology
Thymocytes metabolism
Transcriptome immunology
Cell Differentiation immunology
Cullin Proteins immunology
Proto-Oncogene Proteins c-bcl-6 immunology
T-Lymphocytes, Helper-Inducer immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 211
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 24863065
- Full Text :
- https://doi.org/10.1084/jem.20132267