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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结