Lysophosphatidic Acid Regulation of CD8 T cell activation and function

溶血磷脂酸对 CD8 T 细胞活化和功能的调节

• 批准号: 10116268
• 负责人: Raul Martin Torres
• 金额: $ 51.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116268
• 关键词: ARHGEF1 gene; Antibody Response; Antigens; Bacterial Infections; Biochemical; CD8-Positive T-Lymphocytes; Cells; Cellular biology; Chronic; Cytoplasmic Granules; Cytoskeletal Modeling; Cytotoxic T-Lymphocytes; Enzymes; Event; Functional disorder; G-Protein-Coupled Receptors; Genetic Transcription; Goals; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunotherapy; Impairment; Individual; Infection; Inflammatory; Lead; Lipids; Lymphocytic choriomeningitis virus; Lysophosphatidic Acid Receptors; Lysophospholipids; Lytic; Major Histocompatibility Complex; Malignant Neoplasms; Memory; Molecular; Mus; Pathogenicity; Peptide/MHC Complex; Peptides; Physiological; Play; Production; Receptor Signaling; Regulation; Reticular Cell; Role; Signal Pathway; Signal Transduction; Site; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Vaccines; Viral; Virus; Virus Diseases; Wild Type Mouse; Work; adaptive immune response; adaptive immunity; antigen-specific T cells; chronic infection; cytokine; cytotoxic; cytotoxic CD8 T cells; design; effector T cell; experimental study; extracellular; global health; immune checkpoint blockade; improved; in vivo; lysophosphatidic acid; novel; pathogen; pathogen exposure; pre-clinical; programs; receptor; response; secondary lymphoid organ; small molecule; small molecule inhibitor; success; trafficking; translational study; tumor

PROJECT SUMMARY Cytotoxic CD8 T lymphocytes fill a crucial role in adaptive immunity by virtue of their ability to recognize and eliminate pathogen-infected cells and nascent tumors. To accomplish this important function, the T cell antigen receptor (TCR) expressed by CD8 T cells must recognize a pathogen-derived peptide in the context of the major histocompatibility complex (MHC) class I receptor (pMHC). In response to a pathogen infection this TCR-pMHC recognition event by CD8 T cells is crucial in dictating how the ensuing adaptive response manifests. Thus, TCR signaling by naïve CD8 T cells is not only important in initiating a protective response but TCR signaling by effector CD8 T cells also underlies its cytotoxic activity for the efficient elimination of infected cells. Accordingly, appropriate TCR-signaling is central for the activation, robust proliferation and function of effector and memory CD8 T cells that ultimately leads to the trafficking of pathogen-specific CD8 T cells to sites of infection and elimination of infected cells via CD8 T cell cytolytic activity. Work from our lab has revealed that an endogenous extracellular lysophospholipid, lysophosphatidic acid (LPA), signals via the LPAR5 G-protein coupled receptor expressed by mature human and mouse T cells and negatively regulates TCR signaling, proliferation and cytotoxic activity. Notably, this lipid and the secreted enzyme responsible for its synthesis are often elevated in inflammatory settings including a number of chronic pathogen infections. Yet, how LPA regulates CD8 T cell biology at these pathophysiological levels or at homeostatic endogenous levels has only been cursorily examined and is not well understood. The experiments described in this proposal are designed to provide a comprehensive understanding of the molecular mechanisms by which the LPAR5 signaling negatively impacts TCR signaling and in vivo CD8 T cell immunity. In addition, given that LPA levels are often increased in chronic infections, we also propose to determine if pathogens that establish chronic infections subvert LPA production to suppress T cell immunity and whether small molecule inhibitors are able to antagonize LPAR5 signaling to promote enhanced immunity. The successful completion of these studies is thus expected to not only extend our current understanding of how CD8 T cells are regulated to provide protective immunity against pathogen infections but also may reveal new avenues of therapeutic intervention that may enhance immunity to persistent infections of global health concern.

项目概要 细胞毒性 CD8 T 淋巴细胞凭借其识别能力在适应性免疫中发挥着至关重要的作用。 并消除病原体感染的细胞和新生肿瘤。为了完成这一重要功能，T 细胞 CD8 T 细胞表达的抗原受体 (TCR) 必须识别病原体衍生的肽 主要组织相容性复合体 (MHC) I 类受体 (pMHC)。为了应对病原体感染， CD8 T 细胞的 TCR-pMHC 识别事件对于决定随后的适应性反应至关重要 体现出来。因此，幼稚 CD8 T 细胞的 TCR 信号传导不仅对于启动保护性反应很重要 但效应 CD8 T 细胞的 TCR 信号转导也是其细胞毒活性的基础，可有效消除 被感染的细胞。因此，适当的 TCR 信号传导对于激活、稳健增殖和 效应和记忆 CD8 T 细胞的功能，最终导致病原体特异性 CD8 T 的运输 细胞到达感染部位并通过 CD8 T 细胞的溶细胞活性消除感染细胞。 我们实验室的工作表明，内源性细胞外溶血磷脂，溶血磷脂 酸 (LPA)，通过成熟人类和小鼠 T 细胞表达的 LPAR5 G 蛋白偶联受体发出信号 并对 TCR 信号传导、增殖和细胞毒活性产生负调节。值得注意的是，这种脂质和分泌的 负责其合成的酶在炎症环境中通常会升高，包括许多慢性炎症 病原体感染。然而，LPA 如何在这些病理生理水平或在 内源性稳态水平仅被粗略地研究过并且还没有被很好地理解。实验 该提案中描述的目的是为了提供对分子的全面理解 LPAR5 信号传导对 TCR 信号传导和体内 CD8 T 细胞免疫产生负面影响的机制。 此外，鉴于慢性感染时 LPA 水平通常会升高，我们还建议确定是否 建立慢性感染的病原体会破坏 LPA 的产生以抑制 T 细胞免疫，以及是否 小分子抑制剂能够拮抗LPAR5信号传导以促进增强免疫力。 因此，这些研究的成功完成预计不仅会扩展我们目前的 了解如何调节 CD8 T 细胞以提供针对病原体感染的保护性免疫，但是 还可能揭示治疗干预的新途径，从而增强对持续感染的免疫力 全球健康关注。