Role of TGFBR3 in T-cell development and immune response

描述(由申请人提供)：这项探索性建议的目标是研究转化生长因子R3，也称为β-聚糖，在T细胞发育和免疫反应中的作用。尽管转化生长因子R3在先天免疫系统和获得性免疫系统的细胞中广泛表达，但人们对其在免疫中的作用知之甚少。转化生长因子R3在多种肿瘤中的表达缺失与预后不良有关。我们最近报道了胸腺细胞中转化生长因子R3的表达是受发育调节的，阻断其信号转导导致T细胞成熟的抑制。转化生长因子R3缺失的小鼠表现出胚胎致死性，这阻碍了确定其在免疫系统中的功能的研究。我们开发了一种新的条件性转化生长因子R3fl/fl小鼠，它提供了在所选组织中选择性地针对转化生长因子R3失活的机会。我们发现，在成年小鼠中诱导失活的转化生长因子？R3会导致T细胞发育的深刻变化。在成熟T细胞中，转化生长因子R3的失活促进了Th1的分化，但抑制了Th17的分化。这些结果揭示了转化生长因子R3在T细胞发育和分化中不可或缺的作用。转化生长因子R3是一种辅助受体，可增强转化生长因子-β家族分子与转化生长因子-1/转化生长因子-2异二聚体的结合，从而启动细胞内信号。转化生长因子R3还与高亲和力的抑制素结合，以对抗激活素依赖的信号转导。除了与转化生长因子r1/转化生长因子r2相关的活性外，转化生长因子r3还可以独立地调节与激活和迁移相关的细胞内信号。这一建议的具体目的是：(1)确定转化生长因子R3在T细胞发育和选择中的作用；(2)确定转化生长因子R3在调节天然T细胞向效应细胞分化和自身免疫中的作用。我们拟议的研究将推动我们对转化生长因子-β家族蛋白生物学特性的理解，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.