Maternal T cell recognition of placental antigen

项目摘要。胎盘脱落大量的“外来”蛋白质进入母体循环， 妊娠，由母体抗原呈递细胞（APC）摄取和呈递。值得注意的是， 随后的T细胞应答既不是免疫原性的，也不是致耐受性的，因为怀孕的小鼠既没有被免疫 抗原（Ag），即使在给予强佐剂和耗尽调节性T细胞时，它们也不会成为 因此，胎盘Ag最好被认为是“非免疫原性的”，这是一个潜在的独特类别， 明确的生理前因本提案的目的是阐明细胞和分子基础 为什么胎盘抗原没有免疫原性这个问题对于理解胎盘和胎儿 避免免疫排斥，并且通常也与外周免疫耐受有关。因此， 完全符合Rizzuto博士的长期目标，即了解妊娠的免疫发病机制 并发症和开发用于移植、肿瘤免疫学和自身免疫的新疗法。的 该提案的总体假设是，胎盘抗原的非免疫原性可以通过其 本发明的目的是提供一种能够调节母体APC的物理/生物化学性质和/或表型的抗体，并且具有三个特定的目的。 在目标1中，Rizzuto博士将研究控制CD 4 + T细胞应答的Ag呈递途径， 确定为什么这些是非免疫原性的。该目标建立在初步数据的基础上，即B细胞而不是 DC对于将胎盘Ag呈递给母体CD 4 + T细胞至关重要。在目标2中，她将定义 胎盘抗原的物理/生化特性，使其非免疫原性，包括探索 她发现Ag积累母体抗体的功能意义。在目标3中，她将定义 控制CD 8 + T细胞应答的Ag交叉呈递途径，并确定为什么这些是非免疫性的。 免疫原性。该目标集中于已知交叉呈递Ag的经典Batf 3依赖性DC子集，如 以及目前未定义的非典型APC。这项工作与NIAID的使命有关，因为它将 显著扩展了对外周免疫耐受机制的理解。 Rizzuto博士是加州大学旧金山弗朗西斯科的医学博士研究员。她完成 研究生工作在肿瘤免疫学和解剖病理学的临床培训，并正在申请一个指导 临床科学家研究职业发展奖（K 08）。她的训练计划将有助于她达到 目标是成为一名学术医生科学家。该计划包括Adrian Erlebacher博士的指导， 生殖免疫学领域的领先专家;多学科的科学和职业咨询 委员会，包括免疫耐受和胎盘生物学领域的领导者; 生殖、蛋白质组学和生物统计学;参加会议以促进合作;和职业 发展活动。这些活动将为Rizzuto博士提供必要的技能， 她在围产期病理学方面的临床专业知识不断增长。

Project summary. The placenta sheds a vast amount of “foreign” protein into maternal circulation during pregnancy, to be taken up and presented by maternal antigen presenting cells (APCs). Remarkably, the ensuing T cell response is neither immunogenic nor tolerogenic as pregnant mice neither become immunized to the antigen (Ag), even when given strong adjuvants and depleted of regulatory T cells, nor do they become tolerized to it. Thus, placental Ag is best considered “non-immunogenic,” a potentially unique category without clear physiological antecedent. The objectives of this proposal are to elucidate the cellular and molecular basis for why placental Ag is non-immunogenic. This question is central to understanding how the placenta and fetus avoid immune rejection, and is also relevant to peripheral immune tolerance in general. As such it aligns perfectly with the long-term goal of Dr. Rizzuto which is to understand the immune pathogenesis of pregnancy complications and develop new therapies for use in transplantation, tumor immunology, and autoimmunity. The overall hypothesis of the proposal is that the non-immunogenicity of placental Ag can be explained by its physical/biochemical properties and/or the phenotype of the maternal APC, and has three specific aims. In Aim 1, Dr. Rizzuto will investigate the Ag presentation pathways governing CD4+ T cell responses and determine why these are non-immunogenic. This Aim builds upon preliminary data that B cells rather than DCs are critical for presenting placental Ag to maternal CD4+ T cells. In Aim 2, she will define the physical/biochemical properties of placental Ag that render it non-immunogenic, including exploring the functional significance of her finding that the Ag accumulates maternal antibodies. In Aim 3, she will define the Ag cross-presentation pathways that govern CD8+ T cell responses and determine why these are non- immunogenic. This Aim focuses on the classical Batf3-dependent DC subset known to cross-present Ag, as well as a currently undefined, and atypical APC. This work is relevant to the mission of NIAID because it will significantly expand the understanding of peripheral immune tolerance mechanisms. Dr. Rizzuto is an MD PhD research fellow at the University of California, San Francisco. She completed graduate work in tumor immunology and clinical training in anatomic pathology and is applying for a Mentored Clinical Scientist Research Career Development Award (K08). Her training plan will foster the attainment of her goal of becoming an academic physician scientist. This plan includes mentorship by Dr. Adrian Erlebacher, a leading expert in the field of reproductive immunology; scientific and career advisory by a multidisciplinary committee that includes leaders in the fields of immune tolerance and placental biology; coursework in reproduction, proteomics, and biostatistics; attendance at meetings to foster collaboration; and career development activities. These activities will provide Dr. Rizzuto with the necessary skills to merge her immunology research with her growing clinical expertise in perinatal pathology.