In Vivo Function of the B7 Family of Costimulators

B7 共刺激器家族的体内功能

• 批准号: 7846544
• 负责人: Arlene H. Sharpe
• 金额: $ 2.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846544
• 关键词: Address; Adoptive Transfer; Affect; Attenuated; Autoimmune Diseases; Autoimmunity; Behavior; CD4 Positive T Lymphocytes; Cells; Clinical; Data; Defect; Development; Disease; Dose; Effector Cell; Employee Strikes; Encephalomyelitis; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Family; Family member; Generations; Goals; Grant; Homing; Immune response; In Vitro; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-2; Lead; Ligands; Lymphoid; Mus; Nose; Optic Neuritis; Oral; Organ; Pathogenicity; Pathway interactions; Peptides; Peripheral; Production; Regulation; Relative (related person); Research Personnel; Resistance; Role; Secondary to; Signal Transduction; T-Cell Activation; T-Lymphocyte; Th1 Cells; Tissues; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; cytokine; feeding; in vivo; insight; interleukin-23; migration; novel; oligodendrocyte-myelin glycoprotein; protective effect; research study; response; tool

The overall goal of this application is to dissect the functional roles of the recently identified B7/CD28 family members ICOS and PD-L1 in regulating mucosal tolerance. This focus is driven by our recent studies that have identified essential, non-redundant roles for ICOS and PD-L1 in mucosal tolerance. We have found that ICOS and PD-L1 have similar roles in controlling the ability of orally-induced regulatory T cells to exert their protective effects. Each of these roles must be unique, since orally induced WT CD4+ Treg cannot function following transfer into ICOS-/- or PD-L1-/- mice. In contrast, PD-L1, but not ICOS, is required for the generation of functional orally induced CD4+ Treg. To investigate the relationships between ICOS and PD- L1 in regulating mucosal tolerance, we will analyze the 1) role of ICOS in the generation and/or function of pathogenic effector T cells (IL-12 driven IFN-g producing Th1 cells and IL-23 driven ThlL-17 cells), since the impaired function of orally induced WT CD4+ T reg could be a primary defect or secondary to enhanced pathogenicity of ICOS-/- effector cells 2) role of ICOS in controlling function of orally induced CD4+ Treg; and 3) relationships between ICOS and PD-L1 in controlling functions of self reactive effector and orally induced CD4+ T reg. These studies should reveal the relative roles of ICOS and PD-L1 in controlling the balance between regulatory and encephalitogenic Th1 cells in vivo. We have assembled a number of novel tools that will enable us to address these issues. To dissect the role of ICOS in mucosal tolerance, we have developed ICOS-/- mice. Our PD-L1-/- mice will serve as a definitive tool to examine how PD-L1 regulates the generation and function of orally-induced CD4+ Treg. We will use MOG35-55 specific TCR transgenic mice to visualize the effects of ICOS and PD-L1 dysregulation on activation, migration and expansion of naive and effector T cells in vivo, and development and behavior of orally induced Treg. These studies should lead to insights into how ICOS and PD-L1 regulate the responses of self-reactive T cells.

本应用程序的总体目标是剖析最近发现的B7/CD28家族的功能角色