Vitamin A and acquired immune privilege

维生素A缺乏会导致免疫力的病理改变。只是在过去的一年里， 维甲酸(RA)，一种维生素A代谢物，显著促进了细胞的分化 效应者，CD4+T细胞(T细胞)，AECD4+，适应性调节T细胞(ATREG)。鉴于这一认识， Treg对人类健康和疾病的深远重要性，以及RA对 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影响免疫的核心。这项提议将发现 维生素A缺乏和免疫的潜在分子、细胞和免疫学后果 补充剂对Treg分化与外周免疫耐受的影响。具体目标 将确定：1)控制RA诱导T细胞分化的分子机制 AETreg。我们已经证明，RA显著提高了ATREG的频率。初步调查结果 提示RAR？和RXR？是Treg诱导的关键受体。这些因素的作用 Treg功能中的受体也将使用RAR/RXR的特定抑制剂和激动剂来确定 作为在RAR/RXR信号中受到遗传损害的T细胞。我们还假设RA诱导了 通过差异基因表达和细胞因子改变将Treg分化为“效应器”Treg 制作，归宿和对Treg血统的不可逆转的承诺。2)在体内的影响 维生素A的消耗和补充对外周T细胞耐受性的影响。在一个 Treg依赖的同种异体移植耐受模型：维生素A缺乏导致耐受性丧失和移植物 拒绝。与我们的体外数据一致，我们假设维生素A缺乏会阻止体内的 同种异体特异性Treg的分化。我们试图在同种异体移植的活体模型中证明这一假设。 同种异体特异性Treg的分化和功能可以通过严谨的研究和 量化的。我们已经确定了多种遗传模型，在这些模型中，RA信号在T细胞、CD4+T细胞和 Foxp3+T细胞可以在体内被特异性地操纵，从而导致RA依赖的T细胞信号转导 和外围设备的耐受性。3)区域LN内RA合成的调节和免疫 特权的微环境。我们认为，在免疫中，造血细胞合成RA 特权的微环境控制着Treg的分化。因此，我们建议，造血术 移植物微环境或局部LN内的细胞通过RA控制TeffAETreg的分化 体内合成，并因果地暗示特定细胞类型的RA的产生与 移植物耐受性。我们还将评估调节细胞周期的因素(细胞因子、趋化因子等)。 控制RA产生的关键酶途径的表达。这样的研究将提供有价值的 对RA激动剂和拮抗剂在免疫相关疾病管理中的使用的见解。

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.