Role of TGFBR3 in T-cell development and immune response

TGFBR3 在 T 细胞发育和免疫反应中的作用

• 批准号: 8721608
• 负责人: Chander Raman
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721608
• 关键词: Ablation; Activins; Address; Adult; Affect; Affinity; Apoptosis; Autoimmunity; B-Lymphocytes; Binding; Biological; Biology; Breeding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cell surface; Cells; Congenital Heart Defects; Data; Development; Disease; Distal; Effector Cell; Embryo; Exhibits; Experimental Autoimmune Encephalomyelitis; Family; Fetal Thymic Organ Culture; Generations; Goals; Growth Factor Receptors; Homeostasis; Immune response; Immune system; Immunity; In Vitro; Interruption; Knockout Mice; Knowledge; Lead; Ligands; Malignant Neoplasms; Mature T-Lymphocyte; Modeling; Multiple Sclerosis; Mus; Peripheral; Population; Property; Protein Family; Proteins; Publishing; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Staging; T cell response; T-Cell Development; T-Lymphocyte; TGF beta type III receptor; TGFBR3 gene; Testing; Thymus Gland; Tissues; Transforming Growth Factors; Transgenic Mice; inhibin; migration; mouse model; novel; outcome forecast; promoter; public health relevance; receptor; receptor expression; thymocyte

DESCRIPTION (provided by applicant): The goal of this exploratory proposal is to study the role of TGF¿R3, also known as betaglycan, in T-cell development and immune responses. Although TGF¿R3 is broadly expressed in cells of both the innate and adaptive immune system, very little is known about its function in immunity. Loss of expression of TGF¿R3 in several cancers is associated with poor prognosis. We have recently reported that TGF¿R3 expression in thymocytes is developmentally regulated, and interruption of its signaling leads to inhibition o T-cell maturation. TGF¿R3-null mice exhibit embryonic lethality which has hampered studies to determine its function in the immune system. We have developed a novel conditional TGF¿R3fl/fl mouse that offers the opportunity to selectively target the inactivation of TGF¿R3 in tissues of choice. We show that induced inactivation of TGF¿R3 in the adult mouse leads to profound changes in T cell development. In mature T cells, inactivation of TGF¿R3 enhanced Th1 differentiation but diminished Th17 differentiation. These results reveal an indispensable function for TGF¿R3 in T cell development and differentiation. TGF¿R3 is a coreceptor and enhances the binding of TGF-¿ family of molecules to TGF¿R1/TGF¿R2 heterodimer leading initiation of intracellular signals. TGF¿R3 also binds to inhibins with high affinity to antognize activin-dependent signaling. In addition to TGF¿R1/TGF¿R2 associated activity, TGF¿R3 can also independently modulate intracellular signals associated with activation and migration. For this proposal, the specific aims are: (1) to determine the role of TGF¿R3 in T cell development and selection; (2) to determine the role of TGF¿R3 in modulating the differentiation of na¿ve T cells to effector cells and autoimmunity. Our proposed studies will move the field forward in our understanding of the biological properties of TGF-¿ family of proteins with opportunities to develop new strategies for promoting immunity and/or targeting autoimmunity.

描述（由应用程序提供）：该探索性建议的目的是研究TGF¿R3（也称为βlycan）在T细胞开发和免疫调查中的作用。尽管TGF¿R3在先天和适应性免疫抑制系统的细胞中广泛表达，但对其在免疫学中的功能知之甚少。在几种癌症中TGF¿R3表达的丧失与预后不良有关。我们最近报道说，胸腺细胞中TGF¿R3的表达受到调节，其信号传导的中断导致抑制O T细胞的成熟。 TGF¿R3-NULL小鼠暴露了胚胎致死性，该胚胎障碍妨碍了研究以确定其在免疫系统中的功能。我们已经开发了一种新型的条件TGF？R3FL/FL小鼠，该小鼠提供了选择性地靶向选择组织中TGF¿R3的失活的机会。我们表明，在成年小鼠中诱导的TGF¿R3失活会导致T细胞发育的深刻变化。在成熟的T细胞中，TGF¿R3的灭活增强了Th1的分化，但减少了Th17分化。这些结果揭示了TGF¿R3在T细胞发育和分化中必不可少的功能。 TGF¿R3是一种共肽，增强了TGF-分子家族与TGF¿R1/TGF¿R2异二聚体领先的细胞内信号倡议的结合。 TGF¿R3还结合具有高亲和力的抑制，以抗击激活素依赖性信号传导。除了TGF¿R1/TGF¿R2相关活动外，TGF¿R3还可以独立调节与激活和迁移相关的细胞内信号。对于此提案，具体目的是：（1）确定TGF¿R3在T细胞发育和选择中的作用； （2）确定TGF¿R3在调节Na ve T细胞对效应细胞和自身免疫性的分化中的作用。我们提出的研究将在我们对TGF-oo蛋白家族的生物学特性的理解中推动该领域的发展，并有机会制定新的策略来促进免疫和/或靶向自身免疫性。