The IRF - type I interferon system in T cell-mediated immune tolerance

描述（由申请人提供）：先天免疫反应是一种古老的防御系统，由功能不同的子系统组成，这些子系统已经进化到对抗微生物病原体的感染。先天应答通常不是抗原特异性的，由干扰素（IFN）系统和基于细胞的抗病原体对策组成，这些对策有助于在感染早期限制病原体的复制。成功的先天反应促进细胞因子和生长因子的分泌，这些因子和生长因子形成后来的病原体特异性或获得性免疫反应，由B淋巴细胞和t淋巴细胞组成。虽然I型干扰素在清除感染因子中的作用是毋庸置疑的，但在没有微生物存在的情况下，它们在免疫系统中的作用基本上还不太清楚。我们之前报道过缺乏干扰素激活的STAT1转录因子的小鼠对自身免疫的易感性急剧增加。我们最近发现，由胸腺髓质上皮细胞（mTEC）产生的IFN¿-胸腺中IFN¿的主要来源-在自分泌反馈回路中起作用，似乎调节mTEC的成熟。我们最近的研究表明，I型干扰素系统对调节性T细胞的发育有相当大的贡献，这可能有助于各种自身免疫性疾病的发展。我们证明了irf和I型干扰素信号系统在自然和诱导调节性T细胞的发育和功能中的一个新的和关键的参与，这在维持外周耐受性和预防自身免疫中至关重要。因此，我们建议研究irf、IFN和STAT1在Treg细胞发育和功能过程中的独特功能。在Aim 1中，我们将研究STATs和IFN信号成分在天然和诱导Treg细胞发育中的作用。我们将确定T细胞对这些因素的内在需求是否存在，或者它们的发育受损是否源于胸腺结构受损。我们将进一步研究缺乏stat1的FoxP3+细胞无法抑制效应T细胞的机制，以及干扰素是否可以改变传统效应T细胞向诱导Treg细胞的转化。我们的前期实验还显示，随着年龄的增长，irf3缺失导致天然Foxp3+ Treg细胞数量增加。出乎意料的是，虽然IRF3-/-小鼠的天然Treg细胞增加，但我们观察到诱导（适应性）Foxp3+ Treg细胞的产生同时存在缺陷。我们注意到IRF3-/-天然Treg细胞功能正常，但令人惊讶的是，传统的IRF3-/- CD4+T细胞对Treg细胞的抑制具有抗性。因此，我们将在Aim 2中确定IRF3是否以T细胞固有的方式被需要，以及IRF3缺陷的CD4+ T细胞对Treg细胞介导的抑制反应的失败是否由于其他胸腺细胞群中IRF3缺陷而发生的发育改变。预期的结果不仅将揭示Treg细胞发育的一个新方面，而且还将阐明I型干扰素的额外生物学作用。尽管干扰素在临床上被用于治疗自身免疫性疾病，如多发性硬化症，但其潜在机制尚不清楚。拟议的研究将扩展我们对irf和I型干扰素在Treg细胞发育中的贡献的理解，Treg细胞是维持自我耐受性所必需的。

DESCRIPTION (provided by applicant): The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens. The innate response is generally not antigen-specific, and is composed of the interferon (IFN) system, as well as cell-based anti-pathogen countermeasures that serve to restrict the replication of pathogens early in infection. A successful innate response promotes the secretion of cytokines and growth factors that shape the later pathogen-specific, or acquired immune response composed of B- and T-lymphocytes. While the role of type I interferons in the clearance of infectious agents is unquestionable, their role in the immune system in the absence of microbial presence is substantially less well understood. We had previously reported a dramatic increase in susceptibility towards autoimmunity in mice lacking the interferon-activated STAT1 transcription factor. We recently discovered that IFN¿ produced by medullary thymic epithelial cells (mTEC) - a major source of IFN¿ in the thymus - acts in an autocrine feedback loop that appears to regulate mTEC maturation. Our most recent studies revealed a considerable contribution of the type I interferon system to the development of regulatory T cell that is likely to contribute to the development of various autoimmune disorders. We demonstrated a novel and critical involvement of IRFs and the type I interferon signaling system in the development and function of both natural and induced regulatory T cells which are crucial in the maintenance of peripheral tolerance and the prevention of autoimmunity. We therefore propose to investigate the unique functions of IRFs, IFN¿/¿ and STAT1 in the processes of Treg cell development and function. In Aim 1 we will investigate the role of STATs and IFN¿/¿ signaling components in the development of natural and induced Treg cells. We will determine whether T cell intrinsic requirements for these factors exist, or whether their impaired development results from an impaired thymic architecture. We will further investigate the mechanism why STAT1-deficient FoxP3+ cells fail to suppress effector T cells, and whether interferon can alter the conversion of conventional effector T cells into induced Treg cells. Our pilot experiments also revealed that IRF3-deficiency leads to increased natural Foxp3+ Treg cell numbers with progressive age. Unexpectedly, while natural Treg cells were increased in IRF3-/- mice, we observed a concomitant defect in the generation of induced (adaptive) Foxp3+ Treg cells. We noted that IRF3-/- natural Treg cells function normally, but strikingly, conventional IRF3-/- CD4+T cells are resistant to suppression by Treg cell. We will therefore determine in Aim 2 whether IRF3 is required in a T cell-intrinsic manner, and whether the failure of IRF3-deficient CD4+ T cells to respond to Treg cell-mediated suppression is due developmental alteration that occurred due to IRF3-deficiency in other thymic cell populations. The anticipated results will not only shed light onto a novel aspect of Treg cell development but also elucidate an additional biological role of type I interferons. Even though interferons are being used clinically to treat autoimmune diseases such as Multiple Sclerosis, the underlying mechanism is poorly understood. The proposed studies will extend our understanding of the contributions of IRFs and type I interferons in the development of Treg cells that are essential in the maintenance of self-tolerance.