The Role of 4-1BB in T Cell and APC Interactions

4-1BB 在 T 细胞和 APC 相互作用中的作用

• 批准号: 7652056
• 负责人: Michael Croft
• 金额: $ 37.78万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652056
• 关键词: Age; Animals; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biology; Bone Marrow; Bone Marrow Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cancerous; Cell Communication; Cell Differentiation process; Cell Lineage; Cell division; Cell physiology; Cells; Cessation of life; Chimera organism; Complex; Data; Dendritic Cells; Development; Disease; Effector Cell; Equilibrium; Family; Genes; Grant; Hematopoiesis; Homeostasis; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Interleukin-10; Knowledge; Lead; Ligands; Maintenance; Mature T-Lymphocyte; Membrane; Molecular; Molecular Target; Mus; Myelogenous; Myeloid Progenitor Cells; Myelopoiesis; Peripheral; Play; Population; Prevention; Principal Investigator; Regulation; Role; Signal Transduction; Stem cells; Surface; Symptoms; T memory cell; T-Lymphocyte; TNF gene; Testing; Tumor Necrosis Factor Receptor; abstracting; base; cytokine; member; monocyte; novel; pathogen; progenitor; programs; receptor; response

Program Director/Principal Investigator (Last, First, Middle): Croft, Michael 2 R01 AI042944-10A2 PROJECT SUMMARY/ABSTRACT 4-1BB (CD137), a member of the TNFR superfamily, strongly influences immune cell function in many inflammatory situations. 4-1BB was originally described as a costimulatory molecule and binding to its known ligand, 4-1BBL, a member of the TNF family, is thought to enhance immune responses and the cross-talk between T cells and APC. However, recent data have suggested that 4-1BB biology is much more complex, and that 4-1BB can also play a regulatory or negative role during immune responses. With 4-1BB-deficient mice and using T cells that cannot express 4-1BB, we have found that the initial role, and perhaps its primary role, is an inhibitory rather than stimulatory action. The absence of 4-1BB, in gene-deficient animals, leads to deregulated dendritic cell (DC) development; enhanced responsiveness of T cells to specific antigen; and spontaneous inflammation and autoimmune-type symptoms that develop with age. The molecular basis of these inhibitory activities are unknown. We have found that suppression of myelopoiesis and DC differentiation is due to 4-1BBL delivering inhibitory signals to bone marrow progenitor cells. We also hypothesize that 4-1BB signaling to peripheral T cells can generate both effector cells and regulatory T cells depending on the context in which these signals are received. The studies in this grant will investigate how 4-1BB exerts its modulatory actions through bidirectional cross-talk with 4-1BBL that regulate T cell responsiveness to antigen and hematopoiesis. We will determine how 4-1BB interacting with 4-1BBL controls myeloid and monocyte progenitors that lead to dendritic cell development, and how 4-1BB and 4-1BBL interactions modulate the balance between effector and regulatory T cells that may contribute to maintenance of tolerance and prevention of autoimmune disease.

项目总监/首席调查员(最后、第一、中间)：Croft，Michael 2 R01 AI042944-10A2 项目摘要/摘要 4-1BB(CD137)是TNFR超家族的一员，在许多炎症状态下对免疫细胞功能有很强的影响。4-1BB最初被描述为一种共刺激分子，并与其已知的配体4-1BBL结合，4-1BBL是肿瘤坏死因子家族的成员，被认为可以增强免疫反应，并增强T细胞和APC之间的相互作用。然而，最近的数据表明，4-1BB的生物学特性要复杂得多，而且4-1BB也可以在免疫反应中发挥调节或负面作用。对于4-1BB缺陷的小鼠，使用不能表达4-1BB的T细胞，我们发现最初的作用，也许是它的主要作用，是一种抑制作用，而不是刺激作用。在基因缺陷的动物中，4-1BB的缺失会导致树突状细胞(DC)的失控发育，T细胞对特定抗原的反应性增强，以及随年龄增长而发展的自发性炎症和自身免疫型症状。这些抑制活性的分子基础尚不清楚。我们发现抑制骨髓生成和DC分化是由于4-1BBL向骨髓祖细胞传递抑制信号所致。我们还假设，4-1BB信号到外周T细胞可以产生效应细胞和调节性T细胞，这取决于这些信号被接收的环境。这项拨款中的研究将调查4-1BB如何通过与4-1BBL的双向串扰来发挥其调节作用，调节T细胞对抗原和造血的反应。我们将确定4-1BB与4-1BBL如何相互作用控制导致树突状细胞发育的髓系和单核细胞前体细胞，以及4-1BB和4-1BBL相互作用如何调节效应器和调节性T细胞之间的平衡，这可能有助于维持耐受性和预防自身免疫性疾病。