Identification of Casz1 as a Regulatory Protein Controlling T Helper Cell Differentiation, Inflammation, and Immunity
| Autor: | Brenna K. Harrington, Senthil S. Saravanamuthu, Lijin Dong, Pushpa Pandiyan, Natarajan Bhaskaran, Lixin Zheng, Carol J. Thiele, Chunhua Yan, Ying Hu, Peggy S. Zelenka, Vassili Bletsos, Zhihui Liu, Fengchun Ye, Rachel Harris, Aaron Weinberg |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
lcsh:Immunologic diseases. Allergy 0301 basic medicine Chromatin Immunoprecipitation Encephalomyelitis Autoimmune Experimental medicine.medical_treatment Secondary infection Immunology Gene Expression Mice Transgenic Inflammation Biology Th1 Transcriptome Mice 03 medical and health sciences 0302 clinical medicine RAR-related orphan receptor gamma CD4 differentiation T helper cytokine medicine Animals Humans Immunology and Allergy T-helper cell differentiation Cell Lineage transcriptional regulation Original Research Experimental autoimmune encephalomyelitis Immunity High-Throughput Nucleotide Sequencing Cell Differentiation T-Lymphocytes Helper-Inducer T helper cell medicine.disease Cell biology DNA-Binding Proteins 030104 developmental biology Cytokine medicine.anatomical_structure 030220 oncology & carcinogenesis Cytokines Th17 Cells Th17 medicine.symptom lcsh:RC581-607 Transcription Factors |
| Zdroj: | Frontiers in Immunology, Vol 9 (2018) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Popis: | While T helper (Th) cells play a crucial role in host defense, an imbalance in Th effector subsets due to dysregulation in their differentiation and expansion contribute to inflammatory disorders. Here, we show that Casz1, whose function is previously unknown in CD4+ T cells, coordinates Th differentiation in vitro and in vivo. Casz1 deficiency in CD4+ T cells lowers susceptibility to experimental autoimmune encephalomyelitis, consistent with the reduced frequency of Th17 cells, despite an increase in Th1 cells in mice. Loss of Casz1 in the context of mucosal Candida infection severely impairs Th17 and Treg responses, and lowers the ability of the mice to clear the secondary infection. Importantly, in both the models, absence of Casz1 causes a significant diminution in IFN-γ+IL-17A+ double-positive inflammatory Th17 cells (Th1* cells) in tissues in vivo. Transcriptome analyses of CD4+ T cells lacking Casz1 show a signature consistent with defective Th17 differentiation. With regards to Th17 differentiation, Casz1 limits repressive histone marks and enables acquisition of permissive histone marks at Rorc, Il17a, Ahr, and Runx1 loci. Taken together, these data identify Casz1 as a new Th plasticity regulator having important clinical implications for autoimmune inflammation and mucosal immunity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|