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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

基本信息

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
项目类别：
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

项目摘要

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

摘要