PLZF Regulates CCR6 and Is Critical for the Acquisition and Maintenance of the Th17 Phenotype in Human Cells
| Autor: | Paul J. Gardina, Timothy G. Myers, Joshua M. Farber, Hongwei H. Zhang, Satya P. Singh, Chang Hoon Lee, Vijayaraj Nagarajan, Hsinyi Tsang |
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| Rok vydání: | 2015 |
| Předmět: |
Receptors
CCR6 Immunology Population Kruppel-Like Transcription Factors Gene Expression Mice Transgenic chemical and pharmacologic phenomena C-C chemokine receptor type 6 Biology Article Transcriptome Mice T-Lymphocyte Subsets RAR-related orphan receptor gamma Animals Humans Immunology and Allergy Promyelocytic Leukemia Zinc Finger Protein education Transcription factor Genetics Regulation of gene expression education.field_of_study Cell Differentiation hemic and immune systems Acquired immune system Cell biology Enhancer Elements Genetic Phenotype Gene Expression Regulation Gene Knockdown Techniques Th17 Cells Immunologic Memory Chromatin immunoprecipitation NK Cell Lectin-Like Receptor Subfamily B Protein Binding |
| Zdroj: | The Journal of Immunology. 194:4350-4361 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1401093 |
| Popis: | Th17 cells, which express the chemokine receptor CCR6, are implicated in many immune-mediated disorders, such as psoriasis and multiple sclerosis. We found that expression levels of CCR6 on human effector/memory CD4+ T cells reflect a continuum of Th17 differentiation. By evaluating the transcriptome in cells with increasing CCR6, we detected progressive upregulation of ZBTB16, which encodes the broad complex, tramtrack, bric-à-brac–zinc finger transcription factor promyelocytic leukemia zinc finger protein (PLZF). Using chromatin immunoprecipitation for modified histones, p300, and PLZF, we identified enhancer-like sites at −9/−10 and −13/−14 kb from the upstream transcription start site of CCR6 that bind PLZF in CCR6+ cells. For Th cells from adult blood, both in the CCR6+ memory population and in naive cells activated ex vivo, knockdown of ZBTB16 downregulated CCR6 and other Th17-associated genes. ZBTB16 and RORC (which encodes the “master regulator” RORγt) cross-regulate each other, and PLZF binds at the RORC promoter in CCR6+ cells. In naive Th cells from cord blood, ZBTB16 expression was confined to CD161+ cells, which are Th17 cell precursors. ZBTB16 was not expressed in mouse Th17 cells, and Th17 cells could be made from luxoid mice, which harbor an inactivating mutation in Zbtb16. These studies demonstrate a role for PLZF as an activator of transcription important both for Th17 differentiation and the maintenance of the Th17 phenotype in human cells, expand the role of PLZF as a critical regulator in the human adaptive immune system, and identify a novel, essential element in a regulatory network that is of significant therapeutic interest. |
| Databáze: | OpenAIRE |
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