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。本研究的重点是探讨一些能够表达吲哚胺2，3双加氧酶(IDO-ATERATIONAL DCs)的树突状细胞如何抑制T细胞增殖，抑制体内同种异体T细胞反应，以及促进小鼠皮肤移植耐受的分子和细胞机制。表达IDO的细胞在怀孕期间保护胎儿组织免受攻击，并抑制T细胞对肿瘤的免疫。这些研究的意义在于，它们将为自然免疫调节机制提供关键的新见解，这些机制可能被操纵以提供新的治疗方法，以增强抗肿瘤和抗病原体免疫，并促进自身免疫病患者或接受器官或组织移植的患者的耐受性。在已发表的和初步的研究中，我们发现IDO转基因小鼠对同种异体皮肤移植的耐受性增强，而IDO缺陷小鼠在获得性耐受性和CTLA4-Ig介导的同种异体T细胞反应的抑制方面存在缺陷。体外研究表明，CTLA4-Ig处理或与表达表面CTLA4的调节性T细胞(Tregs)共同培养时，小鼠脾DC表达IDO并阻断T细胞的增殖。因此，指导这一提议的假设是CTLA4+Tregs和IDO能力的DC合作形成一个调控网络，抑制效应器T细胞的反应并促进耐受性。目标1中提出的研究探讨了B7结扎后诱导IDO基因表达的机制。目标2的研究考察了IDO能力的DC的次要亚群如何促进显性T细胞抑制，目标3的研究检验了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.