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.

项目总结。胎盘会将大量的“外来”蛋白质排入母体血液循环。 妊娠，由母体抗原提呈细胞(APC)提取和呈递。值得注意的是， 随之而来的T细胞反应既不是免疫原性的，也不是耐受性的，因为怀孕的小鼠既不会免疫 对抗原(Ag)，即使给予强佐剂和耗尽调节性T细胞，它们也不会成为 对此忍耐。因此，胎盘抗原最好被认为是“非免疫原性的”，这是一个潜在的独特类别，没有 明确的生理前兆。这项建议的目的是阐明细胞和分子基础。 为什么胎盘抗原不具有免疫原性。这个问题是理解胎盘和胎儿如何 避免免疫排斥，一般也与外周免疫耐受有关。因此，它与 完全符合里祖托博士的长期目标，即了解妊娠的免疫发病机制 并开发用于移植、肿瘤免疫学和自身免疫的新疗法。这个 该提议的总体假设是胎盘抗原的非免疫原性可以用它的 母体APC的物理/生化特性和/或表型，并有三个具体目标。 在目标1中，里祖托博士将研究控制CD4+T细胞反应的抗原提呈途径和 确定为什么这些是非免疫原性的。这个目标建立在B细胞的初步数据上，而不是 DC在将胎盘抗原呈递给母体CD4+T细胞方面起着关键作用。在《目标2》中，她将定义 胎盘抗原的物理/生化性质使其不具有免疫原性，包括探索 她发现抗原积聚了母体抗体的功能意义。在《目标3》中，她将定义 支配CD8+T细胞反应的Ag交叉提呈通路，并确定为什么这些反应是非 免疫原性。这一目标集中在已知交叉存在Ag，As的经典的BATF3依赖的DC子集上 以及目前未定义的和非典型的APC。这项工作与NIAID的任务相关，因为它将 显著扩展了对外周免疫耐受机制的理解。 里祖托博士是加州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临床培训的研究生工作，正在申请一名导师 临床科学家研究职业发展奖(K08)。她的训练计划将促进她的成就 目标是成为一名学术内科科学家。该计划包括禤浩焯·埃尔巴赫博士的指导， 生殖免疫学领域的顶尖专家；多学科的科学和职业咨询 包括免疫耐受和胎盘生物学领域的领导者的委员会；课程工作 生殖、蛋白质组学和生物统计学；出席促进合作的会议；以及职业 发展活动。这些活动将为里祖托博士提供必要的技能，使她 随着她在围产期病理学方面的临床专业知识的增长，她进行了免疫学研究。

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