TNF and inflammation

肿瘤坏死因子和炎症

• 批准号: 10262585
• 负责人: Jonathan Ashwell
• 金额: $ 46.93万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262585
• 关键词: 2019-nCoV; Adopted; Adoptive Transfer; Ankylosing spondylitis; Apoptotic; Autoimmune Process; Autoimmune encephalitis; Blocking Antibodies; CD4 Positive T Lymphocytes; CXCL3 gene; Cell Surface Receptors; Cells; Colitis; Collagen Arthritis; Couples; Death Domain; Disease; Evaluation; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-4; Knockout Mice; Malignant Neoplasms; Modeling; Mus; Pathogenicity; Pathologic; Pathway interactions; Psoriasis; Receptors, Tumor Necrosis Factor, Type II; Regulation; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Role; Shapes; Signal Transduction; T-Lymphocyte; T-bet protein; TNF gene; Tumor Necrosis Factor Receptor; Tumor-infiltrating immune cells; Virus Diseases; cytokine; in vivo; macrophage; single-cell RNA sequencing; transcriptome sequencing; transcriptomics

CD4+ T cells are "skewed" to different "T helper" (Th) fates by activating them in the presence of certain cytokine cocktails. Among the best studied Th subsets are Th1 (master transcription factor: T-bet, signature cytokine: IFN-gamma), Th2 (GATA-3 and IL-4), and Th17 (RORgt and IL-17). Th17 cells can be further roughly divided into non-pathogenic and pathogenic cells. The former express immunosuppressive IL-10 whereas the latter express inflammatory products such as GM-CSF and CXCL3. We have found that when naive CD4+ murine T cells are skewed in the presence of TNF as the primary cytokine they adopt an inflammatory Th17 state. We are currently using both antibody-blocking and the analysis of knockout mice to determine which TNF receptor is responsible for this. In addition, in vivo studies of various autoimmune inflammatory models (e.g. experimental autoimmune encephalopathy (EAE), colitis due to adoptive transfer of Treg-depleted T cells, collagen-induced arthritis) with the corresponding TNFR knockout mice are planned to determine the role of TNF signaling in pathological Th skewing. Evaluation of the composition of immune cell infiltrates as well as transcriptomic analysis, both bulk RNA sequencing (RNA-seq) and single cell RNA sequencing (scRNA-seq), will provide a precise picture of how TNF regulation of Th skewing alters the adaptive and innate immune responses.

CD4+ T细胞通过在某些细胞因子鸡尾酒的存在下激活它们来“偏向”不同的“ T助手”（Th）命运。最佳研究子集包括TH1（主转录因子：T-BET，签名细胞因子：IFN-GAMMA），TH2（GATA-3和IL-4）和TH17（RORGT和IL-17）。 Th17细胞可以进一步大致分为非病原和致病细胞。前明确的免疫抑制IL-10，而后者表示诸如GM-CSF和CXCL3之类的表达炎症产品。我们发现，当幼稚的CD4+鼠T细胞在TNF存在的存在中偏向于主要细胞因子时，他们会采用炎症性Th17态。我们目前正在使用抗体阻滞和敲除小鼠的分析来确定哪种TNF受体负责。此外，对各种自身免疫性炎症模型的体内研究（例如，实验性自身免疫性脑病（EAE），由于tnfr敲除小鼠的胶原蛋白T细胞的继发性转移而导致的结肠炎，胶原蛋白诱导的关节炎），以确定TNF信号的作用。对免疫细胞浸润的组成以及转录组分析的评估，Bulk RNA测序（RNA-SEQ）和单细胞RNA测序（SCRNA-SEQ）都将提供偏斜调节的精确图景，从而改变偏斜的调节。