A negative feedback loop mediated by the Bcl6–cullin 3 complex limits Tfh cell differentiation
| العنوان: | A negative feedback loop mediated by the Bcl6–cullin 3 complex limits Tfh cell differentiation |
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| المؤلفون: | Rebecca Mathew, Seth T. Scanlon, Kristin Hollister, Benjamin D. McDonald, Alexander L. Dent, Albert Bendelac, Aaron R. Dinner, Jeffrey J. Bunker, Michael G. Constantinides, Jeffrey D. Singer, Andrew H. Chiang, Ai-Ping Mao, Clara Bertozzi-Villa |
| المصدر: | The Journal of Experimental Medicine |
| بيانات النشر: | Rockefeller University Press, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Cellular differentiation, T cell, Blotting, Western, Immunology, Receptors, Antigen, T-Cell, Mice, Inbred Strains, Mice, Transgenic, Biology, Article, Mice, immune system diseases, hemic and lymphatic diseases, BATF, medicine, Animals, Humans, Immunology and Allergy, Promoter Regions, Genetic, Transcription factor, Oligonucleotide Array Sequence Analysis, Feedback, Physiological, Mice, Knockout, Thymocytes, Reverse Transcriptase Polymerase Chain Reaction, Cullin Proteins, Cell Differentiation, T-Lymphocytes, Helper-Inducer, BCL6, Molecular biology, 3. Good health, Mice, Inbred C57BL, Thymocyte, Basic-Leucine Zipper Transcription Factors, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-6, Transcriptome, Spleen, CD8, HeLa Cells, Protein Binding |
| الوصف: | Bcl6 and E3 ligase cullin 3 complexes mediate negative feedback regulation during thymocyte development and T cell activation to restrain exaggerated Tfh responses. 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. |
| تدمد: | 1540-9538 0022-1007 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a8748e13730cba52dfd3555836c4ddb8Test https://doi.org/10.1084/jem.20132267Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a8748e13730cba52dfd3555836c4ddb8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15409538 00221007 |
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