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 β R3（也称为β聚糖）在T细胞发育和免疫应答中的作用。虽然TGF β R3在先天性和适应性免疫系统的细胞中广泛表达，但对其在免疫中的功能知之甚少。在一些癌症中，TGF β R3表达的缺失与不良预后相关。我们最近报道了TGF β R3在胸腺细胞中的表达受发育调节，其信号传导的中断导致T细胞成熟的抑制。TGF β R3-null小鼠表现出胚胎致死性，这阻碍了确定其在免疫系统中功能的研究。我们已经开发了一种新的条件性TGF <$R3 fl/fl小鼠，其提供了选择性靶向所选组织中TGF <$R3失活的机会。我们表明，诱导成年小鼠TGF？R3失活导致T细胞发育的深刻变化。在成熟T细胞中，TGF β R3的失活增强了Th 1分化，但减少了Th 17分化。这些结果揭示了TGF β R3在T细胞发育和分化中不可或缺的功能。TGF <$R3是一种辅助受体，可增强TGF-<$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。TGF β R3也以高亲和力结合到β-受体结合蛋白以拮抗激活素依赖性信号传导。除了TGF？R1/TGF？R2相关活性，TGF β R3也可以独立调节与活化和迁移相关的细胞内信号。对于该提议，具体目标是：（1）确定TGF <$R3在T细胞发育和选择中的作用;（2）确定TGF <$R3在调节幼稚T细胞分化为效应细胞和自身免疫中的作用。我们提出的研究将推动我们对TGF-β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.