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: 10574540
• 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/10574540
• 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; 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; Proliferating; Receptor Signaling; Regulation; Reticular Cell; Role; Signal Induction; 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; antagonist; 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.

项目摘要 细胞毒性CD8 T淋巴细胞赋予适应性免疫学在适应性免疫学中的关键作用 并消除病原体感染的细胞和新生肿瘤。为了实现这一重要功能，T单元 CD8 T细胞表达的抗原受体（TCR）必须在病原体衍生的肽中 主要的组织相容性复合物（MHC）I类受体（PMHC）。为了应对病原体感染这 CD8 T细胞的TCR-PMHC识别事件对于决定如何确保适应性反应至关重要 表现出来。那就是，幼稚的CD8 T细胞的TCR信号不仅在启动保护性响应中很重要 但是效应子CD8 T细胞的TCR信号传导也构成了其细胞毒性活性的基础，以有效评估 感染细胞。根据某些确定，适当的TCR信号对于激活，鲁棒增殖和 效应子和记忆CD8 T细胞的功能最终导致病原体特异性CD8 T的运输 细胞通过CD8 T细胞溶液活性到感染部位并消除感染细胞。 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），通过成熟的人和小鼠T细胞表达的LPAR5 G蛋白偶联受体的信号 负调节TCR信号传导，增殖和细胞毒性活性。值得注意的是，这种脂质和分泌的 负责其合成的酶通常在炎症环境中升高，包括多种慢性 病原体感染。然而，LPA如何在这些病理生理水平或在 稳态内源性水平只经过了修复的检查，并且尚未得到很好的理解。实验 本提案中描述的旨在提供对分子的全面理解 LPAR5信号传导会对TCR信号传导和体内CD8 T细胞免疫史产生负面影响的机制。 另外，鉴于LPA水平在慢性感染中经常升高，我们还建议确定是否是否 建立慢性感染的病原体颠覆LPA的产生以抑制T细胞免疫以及是否是否 小分子抑制剂能够拮抗LPAR5信号传导以促进免疫力。 因此，预计这些研究的成功完成不仅会扩展我们的当前 了解如何调节CD8 T细胞以提供针对病原体感染的保护免疫，但 还可能揭示了治疗干预的新途径，这可能会增强对持续感染的免疫力 全球健康问题。