Scientific reports, 2017-05, Vol.7 (1), p.1628-14, Article 1628
2017
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- Autor(en) / Beteiligte
- Titel
- Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8 + Treg cells
- Ist Teil von
- Scientific reports, 2017-05, Vol.7 (1), p.1628-14, Article 1628
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4 Treg cells are well characterized whereas the role of CD8 Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8 FOXP3 Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4 Treg cells. But how FOXP3 is induced and maintained in tumor-CD8 Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8 lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8 T cells. Whereas in CD8 Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/s41598-017-01788-zTitel-ID: cdi_doaj_primary_oai_doaj_org_article_b98775057ebd4917908002096e8aef98
- Format
- –
- Schlagworte
- Adolescent, Adult, Animals, Base Sequence, Breast cancer, Breast Neoplasms - immunology, Breast Neoplasms - pathology, Cancer, CD4 antigen, CD8 antigen, CD8-Positive T-Lymphocytes - metabolism, Central nervous system, Chromatin, Conserved Sequence - genetics, Core Binding Factor Alpha 3 Subunit - metabolism, DNA, Intergenic - genetics, Female, Forkhead Transcription Factors - genetics, Forkhead Transcription Factors - metabolism, Foxp3 protein, GATA-3 protein, GATA3 Transcription Factor - metabolism, Gene Expression Regulation, Gene regulation, Humans, Immunoregulation, Immunosuppression Therapy, Immunotherapy, Interleukin-2 Receptor alpha Subunit - metabolism, Lymphocytes T, Mice, Inbred BALB C, Middle Aged, Models, Genetic, Promoter Regions, Genetic, Runx3 protein, Smad3 protein, Smad3 Protein - metabolism, T-Lymphocytes, Regulatory - metabolism, Transcription factors, Transcription, Genetic, Tumor Microenvironment, Young Adult