Role of TGFBR3 in T-cell development and immune response

描述（由申请人提供）：本探索性提案的目标是研究TGF¿R3，也称为β -多糖，在t细胞发育和免疫反应中的作用。尽管TGF¿R3在先天免疫系统和适应性免疫系统的细胞中广泛表达，但对其在免疫系统中的功能知之甚少。TGF - R3在几种癌症中的表达缺失与预后不良有关。我们最近报道了TGF - R3在胸腺细胞中的表达受到发育调节，其信号传导中断导致t细胞成熟受到抑制。TGF¿r3缺失的小鼠表现出胚胎致命性，这阻碍了确定其在免疫系统中的功能的研究。我们已经开发了一种新的条件TGF¿R3fl/fl小鼠，它提供了选择性靶向TGF¿R3在选择组织中的失活的机会。我们发现在成年小鼠中诱导TGF¿R3失活导致T细胞发育发生深刻变化。在成熟T细胞中，TGF¿R3的失活增强了Th1的分化，但减弱了Th17的分化。这些结果揭示了TGF¿R3在T细胞发育和分化中不可或缺的功能。TGF- R3是一种辅助受体，可增强TGF- R3家族分子与TGF- R1/TGF - R2异源二聚体的结合，从而引发细胞内信号的启动。TGF¿R3还与高亲和力的抑制素结合，以拮抗激活素依赖性信号。除了TGF¿R1/TGF¿R2相关活性外，TGF¿R3还可以独立调节与激活和迁移相关的细胞内信号。本研究的具体目的是：(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细胞向效应细胞分化和自身免疫中的作用。我们提出的研究将推动我们对TGF-¿蛋白家族生物学特性的理解，并有机会开发促进免疫和/或靶向自身免疫的新策略。

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.