Maternal T cell recognition of placental antigen

母体 T 细胞识别胎盘抗原

• 批准号: 10689485
• 负责人: Gabrielle A Rizzuto
• 金额: $ 6.65万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689485
• 关键词: Adjuvant; Allogenic; Anatomy; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Biochemical; Biometry; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; California; Categories; Cell physiology; Cells; Clinical; Collaborations; Conceptions; Cross Presentation; Data; Dendritic Cells; Doctor of Philosophy; Experimental Models; Exposure to; Fetus; Fostering; Goals; Graft Rejection; Immune; Immune Tolerance; Immune system; Immunity; Immunize; Immunoglobulin G; Immunology; Ingestion; Injections; Intravenous; K-Series Research Career Programs; Knowledge; Lipids; Malignant Neoplasms; Maternal antibody; Mentors; Mentorship; Mission; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nature; Nucleic Acids; Organ Transplantation; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Perinatal; Peripheral; Phenotype; Physicians; Physiological; Placenta; Placental Biology; Plasma; Population; Pregnancy; Pregnancy Complications; Property; Proteins; Proteomics; Regulatory T-Lymphocyte; Reproduction; Reproductive Immunology; Research; Role; San Francisco; Scientist; Spleen; System; T cell response; T-Lymphocyte; Time; Training; Transplantation; Universities; Work; antigen-specific T cells; career; career development; combat; design; experimental study; immune activation; immunogenic; immunogenicity; insight; meetings; mouse model; multidisciplinary; novel; novel strategies; novel therapeutics; pregnant; prevent; receptor; response; skills; tumor immunology; uptake

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.

项目摘要。 lopeta将大量的“异物”蛋白散发到材料循环中 怀孕，由母体抗原呈递细胞（APC）占用并提出。值得注意的是 随之而来的T细胞反应既不是免疫原性的，也不是耐受性，因为怀孕小鼠既没有免疫 对于抗原（Ag），即使给予强大的调节器并耗尽了调节性T细胞，也不会变成 容忍它。这是最好将placenal ag视为“非免疫原性”，这是一个潜在的独特类别，没有 清除身体的前提。该提案的目标是阐明细胞和分子基础 为何lopenal ag是非免疫原性的。这个问题是了解胎盘和胎儿如何 避免免疫排斥反应，并且通常与周围免疫耐受性有关。因此它会对齐 完美地实现了Rizzuto博士的长期目标，即了解怀孕的免疫发病 并发症并开发用于移植，肿瘤免疫学和自身免疫性的新疗法。这 该提案的总体假设是，可以通过其非免疫原性来解释其 物理/生化特性和/或母体APC的表型，具有三个特定的目的。 在AIM 1中，Rizzutto博士将研究管理CD4+ T细胞反应的AG演示途径和 确定为什么这些是非免疫原性的。此目标建立在B细胞而不是B细胞的初步数据的基础上 DC对于向材料CD4+ T细胞呈现位置Ag至关重要。在AIM 2中，她将定义 斑点Ag的物理/生化特性，使其变得非免疫原性，包括探索 她发现Ag积累物物抗体的功能意义。在AIM 3中，她将定义 控制CD8+ T细胞反应的AG交叉呈递途径，并确定为什么这些是非 - 免疫原性。该目标重点介绍经典的bATF3依赖性直流子集已知是交叉出现的AG， 以及当前不确定的和非典型的APC。这项工作与Niaid的使命有关，因为它将 显着扩大对外周免疫耐受机制的理解。 Rizzuto博士是加利福尼亚大学旧金山分校的医学博士研究员。她完成了 肿瘤免疫学和解剖病理学的临床培训的研究生工作，并正在申请指导 临床科学家研究职业发展奖（K08）。她的培训计划将促进她的成就 成为一名学术物理科学家的目标。该计划包括Adrian Erlebacher博士的Mentalship， 生殖免疫学领域的主要专家；多学科的科学和职业咨询 包括免疫耐受性和占地生物学领域的领导者在内的委员会；课程工作 繁殖，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博士提供合并她的必要技能 免疫学研究以其越来越多的围产期病理学临床专业知识。

项目成果

A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function.

• DOI: 10.1038/s41590-023-01444-x
• 发表时间: 2023-04
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Lo, Wan-Lin;Kuhlmann, Miriam;Rizzuto, Gabrielle;Ekiz, H. Atakan;Kolawole, Elizabeth M.;Revelo, Monica P.;Andargachew, Rakieb;Li, Zhongmei;Tsai, Yuan-Li;Marson, Alexander;Evavold, Brian D.;Zehn, Dietmar;Weiss, Arthur
• 通讯作者: Weiss, Arthur

A spatially resolved timeline of the human maternal-fetal interface.

• DOI: 10.1038/s41586-023-06298-9
• 发表时间: 2023-07
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Greenbaum, Shirley;Averbukh, Inna;Soon, Erin;Rizzuto, Gabrielle;Baranski, Alex;Greenwald, Noah F.;Kagel, Adam;Bosse, Marc;Jaswa, Eleni G.;Khair, Zumana;Kwok, Shirley;Warshawsky, Shiri;Piyadasa, Hadeesha;Goldston, Mako;Spence, Angie;Miller, Geneva;Schwartz, Morgan;Graf, Will;Van Valen, David;Winn, Virginia D.;Hollmann, Travis;Keren, Leeat;van de Rijn, Matt;Angelo, Michael
• 通讯作者: Angelo, Michael