Regulation of effector T cell function by Blimp-1 in a murine model of colitis

Blimp-1 在小鼠结肠炎模型中调节效应 T 细胞功能

• 批准号: 7895658
• 负责人: Gislaine A Martins
• 金额: $ 20.31万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895658
• 关键词: Address; Adoptive Transfer; Affect; Age; Antibiotics; Antibodies; Antigens; B lymphocyte-induced maturation protein 1; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Chronic; Colitis; Colon; Complex; Crohn' s disease; Cytokine Receptors; Defect; Development; Disease; Disease Pathway; Effector Cell; Equilibrium; Flow Cytometry; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Programming; Genus Cola; Goals; Homeostasis; Human; Immune system; Immunofluorescence Immunologic; In Situ; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Infiltrate; Inflammatory disease of the intestine; Interleukin-2; Intestinal Mucosa; Intestines; Kinetics; Knockout Mice; Lead; Lymphocyte; Maintenance; Mesentery; Microarray Analysis; Modeling; Molecular; Molecular Target; Mus; Organ; Organism; Pathogenesis; Pathway interactions; Peripheral; Physiological; Plasma Cells; Production; RNA; Recombinant Cytokines; Regulation; Regulatory T-Lymphocyte; Reporter; Resolution; Retroviridae; Role; Small Interfering RNA; Staining method; Stains; Surface; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Time; Transcription Repressor/Corepressor; Ulcerative Colitis; base; cytokine; experience; in vivo; insight; interest; lymph nodes; microbial; neutralizing antibody; new therapeutic target; novel therapeutic intervention; protein expression; public health relevance; research study; response

DESCRIPTION (provided by applicant): Homeostasis in the intestinal mucosa is maintained by a delicate balance between physiological and pathophysiological inflammation that assures efficient response against pathogenic organisms and avoidance of hyperresponsiveness to the commensal flora. Disruption of this balance results in the development of chronic inflammatory conditions, such as ulcerative colitis and Crohn's disease, collectively termed Inflammatory Bowel Disease (IBD). T lymphocytes are major effector cells in IBD, thus, interfering with T cell function could be a potential strategy to treat IBD. However, the precise mechanisms underlying the uncontrolled T cell responses in IBD are not well understood. We and others have recently identified the transcriptional repressor B Lymphocyte Induced Maturation Protein-1 (Blimp-1) as an important regulator of T cell homeostasis and function. Blimp-1 was first known for its crucial role in the terminal differentiation of antibody-secreting plasma cells. Recent studies show that Blimp-1 is also highly expressed in activated T cells. Mice with a T cell-specific deletion of Blimp-1 accumulate "antigen-experienced" cells in the periphery and spontaneously develop colitis, without compromising other organs, indicating that Blimp-1 is required for proper T cell function at the intestinal mucosal. Based on these findings and previous studies in other cell lineages, which established that Blimp- 1 controls several genetic programs, we hypothesize that in T cells Blimp-1 regulates genetic programs crucially important to control responsiveness in the intestinal mucosa, and identification of genetic targets of Blimp-1 in T cells should reveal new molecular pathways implicated in mucosal homeostasis. In the current proposal we will test this hypothesis through the following specific aims: 1) characterize the colitis in the Blimp-1CKO mice to gain insight into the effector mechanisms disrupted in the absence of Blimp-1; and 2) generate and compare Blimp-1 sufficient and deficient colitogenic T cells to identify and validate genes regulated by Blimp-1 in these cells. To accomplish these aims we will use the Blimp-1 CKO mice we have previously generated. First, we will conduct phenotypical and functional analysis to identify the T cell subpopulations causing disease in these mice. Second, we will use adoptive transfer experiments to generate Blimp-1sufficient and deficient colitogenic T cells to be used in gene expression studies (including RNA microarray) to identify molecular pathways controlled by Blimp-1. We anticipate that upon completion of the experiments proposed here, we will have identified new genetic targets of Blimp-1 in T cells and uncovered new pathways important for the regulation of effector T cell function in the intestinal mucosal. Further exploration of these pathways can lead to the development of new therapeutic approaches to treat IBD and potentially other inflammatory disorders. PUBLIC HEALTH RELEVANCE: Unbalanced T cell responses in the intestines result in chronic inflammation of the GI tract. We are seeking to elucidate regulatory mechanisms that control T cell effector function in the intestinal mucosa. Identification of these mechanisms will contribute to development of new therapeutic approaches to treat IBD.

描述（由申请人提供）：肠粘膜的稳态是通过生理和病理生理炎症之间的微妙平衡来维持的，这确保了对病原微生物的有效反应并避免对共生菌群的过度反应。这种平衡的破坏会导致慢性炎症状况的发展，例如溃疡性结肠炎和克罗恩病，统称为炎症性肠病（IBD）。 T淋巴细胞是IBD的主要效应细胞，因此，干扰T细胞功能可能是治疗IBD的潜在策略。然而，IBD 中 T 细胞反应失控的确切机制尚不清楚。我们和其他人最近发现转录抑制因子 B 淋巴细胞诱导成熟蛋白-1 (Blimp-1) 是 T 细胞稳态和功能的重要调节因子。 Blimp-1 最初因其在抗体分泌浆细胞终末分化中的关键作用而闻名。最近的研究表明，Blimp-1 在活化的 T 细胞中也高表达。 T细胞特异性缺失Blimp-1的小鼠会在外周积聚“经历过抗原”的细胞，并自发发展为结肠炎，而不会损害其他器官，这表明Blimp-1是肠粘膜T细胞正常功能所必需的。基于这些发现和之前对其他细胞谱系的研究，确定了 Blimp-1 控制着多个遗传程序，我们假设，在 T 细胞中，Blimp-1 调节遗传程序，这对于控制肠粘膜的反应性和遗传靶点的识别至关重要。 T 细胞中 Blimp-1 的表达应该揭示与粘膜稳态有关的新分子途径。在当前的提案中，我们将通过以下具体目标来检验这一假设：1）表征Blimp-1CKO小鼠的结肠炎，以深入了解在缺乏Blimp-1的情况下破坏的效应机制； 2) 生成并比较 Blimp-1 充足和缺陷的致结肠炎 T 细胞，以识别和验证这些细胞中受 Blimp-1 调节的基因。为了实现这些目标，我们将使用我们之前生成的 Blimp-1 CKO 小鼠。首先，我们将进行表型和功能分析，以确定导致这些小鼠患病的 T 细胞亚群。其次，我们将使用过继转移实验来生成 Blimp-1 充足和缺陷的致结肠炎 T 细胞，用于基因表达研究（包括 RNA 微阵列），以确定由 Blimp-1 控制的分子途径。我们预计，在完成此处提出的实验后，我们将确定 T 细胞中 Blimp-1 的新遗传靶标，并发现对于调节肠粘膜效应 T 细胞功能重要的新途径。对这些途径的进一步探索可以促进治疗 IBD 和其他潜在炎症性疾病的新治疗方法的开发。公共卫生相关性：肠道内 T 细胞反应不平衡会导致胃肠道慢性炎症。我们正在寻求阐明控制肠粘膜 T 细胞效应功能的调节机制。这些机制的确定将有助于开发治疗 IBD 的新治疗方法。