IDO dependent T cell suppression

描述（由申请人提供）：与这些研究相关的研究项目的长期目标是确定抑制T细胞免疫和促进免疫耐受的自然机制。提出的研究的具体重点是研究分子和细胞机制，解释一些树突状细胞能够表达吲哚胺2，3双加氧酶（IDO主管DC）抑制T细胞增殖，抑制体内同种异体T细胞反应，并促进小鼠皮肤移植耐受性。表达IDO的细胞在妊娠期间保护胎儿组织免受攻击并抑制T细胞对肿瘤的免疫。提出的研究的意义在于，它们将为天然免疫调节机制提供关键的新见解，该机制可以被操纵以提供新的治疗方法来增强抗肿瘤和抗病原体免疫，并促进患有自身免疫性疾病的患者或接受器官或组织同种异体移植的患者的耐受性。在已发表的和初步的研究中，我们表明IDO转基因小鼠表现出对皮肤同种异体移植物的增强的耐受性，而IDO缺陷型小鼠表现出获得性耐受和CTLA 4-Ig介导的同种异体T细胞应答抑制的缺陷。体外进行的研究显示，鼠脾DC的小亚群表达IDO，并且响应于CTLA 4-IG处理或当与表达表面CTLA 4的调节性T细胞（TCL 4）一起培养时阻断T细胞增殖。因此，指导该提议的假设是CTLA 4 + T细胞和IDO-感受态DC协作形成抑制效应T细胞应答并促进耐受性的调节网络。目的1中提出的研究检查了B7连接后诱导IDO基因表达的机制。目的2中的研究检查了IDO感受态DC的次要亚群如何促进显性T细胞抑制，目的3中的研究检查了IDO表达与Treg发育和功能之间的关系。

DESCRIPTION (provided by applicant): The long term objectives of the research project to which these studies relate is to identify natural mechanisms that suppress T cell immunity and promote immune tolerance. The specific focus of studies proposed is to examine molecular and cellular mechanisms that explain how some dendritic cells capable of expressing the enzyme indoleamine 2,3 dioxygenase (IDO-competent DCs) inhibit T cell proliferation, suppress allogeneic T cell responses in vivo, and promote tolerance to skin allografts in mice. Cells expressing IDO protect fetal tissues from attack during pregnancy and suppress T cell immunity to tumors. The significance of studies proposed is that they will provide key new insights into a natural immunoregulatory mechanism that may be manipulated to provide new therapeutic approaches to enhance anti-tumor and anti-pathogen immunity, and to promote tolerance in patients with autoimmune diseases, or who have received organ or tissue allografts, in published and preliminary studies we show that IDO-transgenic mice exhibited enhanced tolerance to skin allografts, while IDO deficient mice exhibited defects in acquired tolerance and CTLA4-Ig-mediated suppression of allogeneic T cell responses. Studies conducted in vitro revealed that minor subsets of murine splenic DCs expressed IDO and blocked T cell proliferation in response to CTLA4-Ig treatment, or when cultured with regulatory T cells (Tregs) expressing surface CTLA4. Hence, the hypothesis that guides this proposal is that CTLA4+ Tregs and IDO-competent DCs collaborate to form a regulatory network that suppresses effector T cell responses and promotes tolerance. Studies proposed in Aim 1 examine the mechanisms that induce IDO gene expression following B7 ligation. Studies in Aim 2 examine how minor subsets of IDO-competent DCs promote dominant T cell suppression and studies in Aim 3 examine the relationship between IDO expression and Treg development and function.