Vitamin A and acquired immune privilege

描述（由申请人提供）：维生素A缺乏导致免疫力的病理改变。仅在去年，已显示视黄酸（RA），维生素A代谢物，显著增强效应子、CD 4 + T细胞（Teff）、AECD 4+、适应性调节性T细胞（aTreg）的分化。鉴于这一认识，Treg对人类健康和疾病的深刻重要性，以及RA对这些细胞的生长和分化的强大影响，我们假设RA对Treg生长，分化和功能的作用是维生素A对免疫力影响的核心。该建议将发现维生素A缺乏和补充对Treg分化和外周免疫耐受的潜在分子，细胞和免疫学后果。具体目的将确定：1）控制RA诱导Teff AETreg分化的分子机制。我们已经表明，RA显着提高aTreg的频率。初步研究结果表明，RAR 1和RXR 1是诱导Treg的关键受体。这些受体在Treg功能中的作用将使用RAR/RXR的特异性抑制剂和激动剂以及在RAR/RXR信号传导中遗传受损的T细胞来确定。我们还假设RA通过差异基因表达、改变的细胞因子产生、归巢和对Treg谱系的不可逆承诺诱导Treg分化为“效应”Treg。2)维生素A消耗和补充对外周T细胞耐受性发展的体内影响。在Treg依赖性同种异体移植物耐受性的模型中，维生素A缺乏导致耐受性丧失和移植物排斥。与我们的体外数据一致，我们假设维生素A缺乏阻止同种异体特异性Treg的体内分化。我们试图在同种异体移植耐受的体内模型中证明这一假设，从而可以严格地研究和量化同种异体特异性Treg的分化和功能。我们已经鉴定了多种遗传模型，其中T细胞、CD 4 + T细胞和Foxp 3 + T细胞中的RA信号传导可以在体内被特异性操纵，以因果地牵连RA依赖性T细胞信号传导和外周耐受。3)局部LN和免疫特权微环境中RA合成的调节。我们提出，RA合成造血细胞在免疫特权微环境控制Treg的分化。因此，我们提出移植物微环境或区域LN内的造血细胞通过体内RA合成控制Teff AETreg分化，并因果地暗示特定细胞类型的RA产生与移植耐受的持续性有关。我们还将评估调节控制RA产生的关键酶途径表达的因素（细胞因子，趋化因子等）。这些研究将为RA激动剂和拮抗剂在免疫相关疾病管理中的应用提供有价值的见解。 公共卫生相关性：许多研究表明，维生素A补充剂通过其对免疫系统的恢复作用降低了传染病的发病率和死亡率。该提案将发现维生素A缺乏和补充对健康和疾病中免疫系统的潜在分子，细胞和免疫学后果。这将为使用这种天然药物治疗免疫相关疾病提供理论基础。

DESCRIPTION (provided by applicant): Vitamin A deficiency results in pathological alterations in immunity. Only in the last year, has it been shown that retinoic acid (RA), a Vitamin A metabolite, dramatically enhances the differentiation of effector, CD4+ T cells (Teff)AECD4+, adaptive regulatory T cells (aTreg). Given this realization, the profound importance of Treg to human health and disease, and the powerful impact that RA exerts on the growth and differentiation of these cells, we hypothesize that the actions of RA on Treg growth, differentiation and function is central to the impact of Vitamin A on immunity. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and supplementation on the differentiation of Treg and peripheral immunologic tolerance. The Specific Aims will determine: 1) The molecular mechanisms which control RA-induced differentiation of Teff AETreg. We have shown that RA dramatically enhances the frequency of aTreg. Preliminary findings indicate that RAR1 and RXR1 are the critical receptors for the induction of Treg. The role of these receptors in Treg function will be determined using specific inhibitors and agonists for RAR/RXR, as well as T cells that are genetically impaired in RAR/RXR signaling. We also hypothesize that RA induces the differentiation of Treg to an "effector" Treg by virtue of differential gene expression, altered cytokine production, homing and an irreversible commitment to the Treg lineage. 2) The in vivo impact of Vitamin A depletion and supplementation on the development of peripheral T cell tolerance. In a model of Treg -dependent allograft tolerance, Vitamin A deficiency results in loss of tolerance and graft rejection. Consistent with our in vitro data, we hypothesize that Vitamin A deficiency prevents the in vivo differentiation of allospecific Treg. We seek to prove this hypothesis in in vivo models of allograft tolerance whereby the differentiation and function of allospecific Treg can be critically investigated and quantified. We have identified multiple genetic models where RA signaling in T cells, CD4+ T cells and Foxp3+ T cells can be specifically manipulated in vivo to causally implicate RA-dependent T cell signaling and peripheral tolerance. 3) Regulation of RA synthesis within the regional LN and the immune privileged microenvironment. We propose that RA synthesis by hematopoietic cells in the immune privileged microenvironment controls the differentiation of Treg. As such we propose that hematopoietic cells within the graft microenvironment or regional LN controls Teff AETreg differentiation through RA synthesis in vivo, and causally implicate the production of RA by a specific cell type to the persistence of graft tolerance. We will also evaluate the factors (cytokines, chemokines, other) that regulate the expression of key enzymatic pathways that control RA production. Such studies will provide valuable insights into the use of RA agonists and antagonists in the management of immune related diseases. PUBLIC HEALTH RELEVANCE: Numerous studies have demonstrated that Vitamin A supplementation reduces morbidity and mortality from infectious diseases through its rejuvenating impact on the immune system. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and repletion on the immune system in health and disease. This will provide a rationale basis for use of this natural medicine on the treatment of immune related disorders.