Vitamin A and acquired immune privilege

维生素A缺乏导致免疫力的病理改变。只是在去年， 表明维生素A代谢产物维甲酸（RA）显着增强了细胞的分化 效应子，CD 4 + T细胞（Teff），AECD 4+，适应性调节性T细胞（aTreg）。鉴于这一认识， Treg对人类健康和疾病的深刻重要性，以及RA对人类健康和疾病的强大影响。 这些细胞的生长和分化，我们假设RA对Treg生长的作用， 分化和功能是维生素A对免疫力影响的核心。该提案将发现 维生素A缺乏的潜在分子、细胞和免疫学后果， 补充对Treg分化和外周免疫耐受的影响。具体目标 将确定：1）RA诱导Teff分化的分子机制 AETreg。我们已经表明，RA显着提高aTreg的频率。初步调查结果 表明RAR <$和RXR <$是诱导Treg的关键受体。这些的作用 将使用RAR/RXR的特异性抑制剂和激动剂，以及 因为T细胞在RAR/RXR信号传导中遗传受损。我们还假设RA诱导了 通过差异基因表达、改变的细胞因子表达和/或细胞因子水平， 生产、归巢和对Treg谱系的不可逆转的承诺。2)体内影响 维生素A消耗和补充对外周T细胞耐受性的发展。中 在Treg依赖性同种异体移植耐受模型中，维生素A缺乏导致耐受丧失， 排斥反应与我们的体外数据一致，我们假设维生素A缺乏阻止了体内 同种异型Treg的分化。我们试图在同种异体移植的体内模型中证明这一假设 耐受性，由此可以严格研究同种异体特异性Treg的分化和功能， 量化。我们已经确定了多种遗传模型，其中T细胞，CD 4 + T细胞和CD 4 + T细胞中的RA信号传导， Foxp 3 + T细胞可以在体内特异性操纵以因果地牵连RA依赖性T细胞信号传导 和外周耐受性。3)局部LN内RA合成的调节和免疫调节 优越的微环境我们认为，RA的合成造血细胞在免疫 特权微环境控制Treg的分化。因此，我们建议， 移植物微环境或局部LN内的细胞通过RA控制Teff AETreg分化 在体内合成，并因果牵连生产的RA由一个特定的细胞类型的持久性， 移植耐受性我们还将评估调节细胞因子（细胞因子，趋化因子，其他）的因素。 表达控制RA产生的关键酶途径。这些研究将提供宝贵的 深入了解RA激动剂和拮抗剂在免疫相关疾病管理中的应用。

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 RAR¿ and RXR¿ 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.