Signaling via MHC: engineering immune cells with new capabilities

通过 MHC 发出信号：改造免疫细胞使其具有新功能

• 批准号: 10472922
• 负责人: Alok joglekar
• 金额: $ 138.38万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472922
• 关键词: Adaptive Immune System; Antigen-Presenting Cells; Antigenic Specificity; Antigens; Autoimmune Diseases; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Communicable Diseases; Complex; Disease; Effectiveness; Engineering; Epitopes; Experimental Models; Genes; Immune; Immunity; Immunologic Monitoring; Lead; Length; Link; Major Histocompatibility Complex; Malignant Neoplasms; Modality; Molecular; Natural Killer Cells; Organ Transplantation; Outcome; Peptide/MHC Complex; Peptides; Play; Role; Signal Transduction; Specificity; Surface; Synthetic immunology; T cell response; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; arm; autoreactivity; cancer transplantation; cellular engineering; combat; combinatorial; cytotoxic CD8 T cells; diagnostic tool; extracellular; frontier; immunoengineering; novel; novel diagnostics; novel therapeutics; pathogen; receptor; response; tool; tumor

ABSTRACT T cells constitute an essential arm of the adaptive immune system, protecting against pathogens and tumors, while tolerating self-tissues. Dysregulation of T cell responses can lead to infectious diseases, cancers, or autoimmune disorders. The key to the effectiveness of T cells is their exquisite antigenic specificity, which can be harnessed to combat diseases. T cells use their surface T cell receptor (TCR) to recognize peptide epitopes on Major Histocompatibility Complex (MHC) molecules (pMHC). While signaling through the TCR and its consequences have been studied extensively, pMHC is conventionally seen as merely a ‘flag’ on target cells for recognition by T cells. MHC molecules do not have canonical intracellular signaling domains, and therefore do not elicit any function into the cells presenting them, making TCR-pMHC interaction a ‘one-way street’ in terms of functional response. This presents a unique engineering opportunity: can TCR-pMHC interactions become ‘two-way streets’? Here, we hypothesize that if pMHC complexes are augmented with signaling domains, they can elicit signaling cascades, leading to expression of response genes that will cause cell-intrinsic functional changes, ultimately leading to cell-extrinsic functional changes. To that end, we will use the engineering platform developed by my group: Signaling and Antigen-presenting Bifunctional Receptors (SABRs). SABRs consist of extracellular full-length MHC complexes with genetically (and hence covalently) linked epitopes, fused with intracellular signaling domains. SABRs can present epitopes to T cells and elicit intracellular signaling upon successful recognition, thereby converting TCR-pMHC interactions into ‘two-way streets. In this proposal, we aim to wield SABRs to impart novel functional capabilities to immune and non-immune cells, thereby opening a new frontier of immune engineering and synthetic immunology. We will first lay out a framework for developing SABRs as a cellular engineering platform to empower combinatorial engineering of immune and non-immune cells to achieve desired immune outcome. We will describe three immune applications of SABRs: 1) engineering of cytotoxic CD8+ T cells or Natural Killer (NK) cells to eliminate autoreactive CD4+ T cells, 2) engineering professional Antigen-Presenting Cells (APCs) to modulate self-reactive or anti-tumor CD8+ T cell responses, 3) engineering CD8+ T cells to sense endogenous immunity to specific antigens and induce a secondary function, leading to a ‘read-and-react’ molecular circuit. These studies will create cellular therapeutic modalities, immune monitoring and perturbation tools, experimental model systems and uncover new immune phenomena. These studies will have profound implications on study and treatment of a wide range of diseases – autoimmune disorders, infectious diseases, cancers, and organ transplantations. 1

抽象的 T细胞构成自适应免疫系统的重要部门，可防止病原体和肿瘤， 同时容忍自我组织。 T细胞反应的失调会导致传染病，癌症或 自身免疫性疾病。 T细胞有效性的关键是它们的独家抗原特异性，这可以 要利用战斗疾病。 T细胞使用其表面T细胞受体（TCR）识别肽表位 在主要的组织相容性复合物（MHC）分子（PMHC）上。通过TCR发出信号 对后果进行了广泛的研究，通常将PMHC视为仅在目标细胞上的“标志” T细胞识别。 MHC分子没有规范的细胞内信号传导域，因此 没有引起呈现它们的单元的任何功能 功能响应。这是一个独特的工程机会：TCR-PMHC互动可以 “双向街道”？在这里，我们假设如果PMHC复合物被信号域增强，则它们 可以引起信号级联反应，导致反应基因的表达，这将引起细胞中性功能 变化，最终导致细胞超支功能变化。为此，我们将使用工程平台 由我的小组开发：信号传导和抗原呈递分叉受体（SABR）。 SABR由 细胞外的全长MHC复合物与一般（因此是共价）连接的表位，与 细胞内信号传导域。 SABR可以向T细胞呈现表位，并引起细胞内信号传导 成功的认可，从而将TCR-PMHC互动转换为“双向街道”。在这个建议中，我们 旨在挥动SABR将新型的功能能力赋予免疫和非免疫细胞，从而打开 免疫工程和合成免疫学的新领域。我们将首先制定一个开发框架 SABR作为一个蜂窝工程平台，以赋予免疫和非免疫的组合工程 细胞达到所需的免疫结果。我们将描述SABR的三种免疫应用：1）工程 细胞毒性CD8+ T细胞或天然杀伤（NK）细胞以消除自动反应性CD4+ T细胞，2）工程 专业的抗原呈递细胞（APC）调节自反应或抗肿瘤CD8+ T细胞反应，3） 工程CD8+ T细胞以对特定抗原感知内源性免疫学并诱导二次功能， 导致“读取和反应”分子电路。这些研究将产生细胞热方式，免疫 监测和扰动工具，实验模型系统以及发现新的免疫现象。这些 研究将对多种疾病的研究和治疗产生深远的影响 - 自身免疫 疾病，传染病，癌症和器官移植。 1