Elucidating the regulatory role of CTLA-4 on Natural Killer cell responses

阐明 CTLA-4 对自然杀伤细胞反应的调节作用

• 批准号: 8645817
• 负责人: Jenny Karo
• 金额: $ 2.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645817
• 关键词: Acquired Immunodeficiency Syndrome; Activated Natural Killer Cell; Antigens; Autoimmune Diseases; B-Lymphocytes; Blocking Antibodies; CD28 gene; CD8B1 gene; Cancer Patient; Cells; Clinical; Communicable Diseases; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocytes; Data; Development; Disease; Effector Cell; Future; Generations; Genes; Goals; Homologous Gene; Hour; Human; Immune response; Immune system; Immunity; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Infection; Knock-in Mouse; Life; Ligands; Ligation; Lymphoid; Lytic; MHC Class I Genes; Malignant Neoplasms; Memory; Modeling; Molecular; Monitor; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Newborn Infant; Organ; Patients; Peptide/MHC Complex; Pharmaceutical Preparations; Phase; Play; Population; Property; Radiation therapy; Research; Research Proposals; Rest; Role; Shapes; Signal Transduction; Stress; System; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Transcript; Transplant Recipients; Vaccination; Viral; Viral Antigens; Virus Diseases; adaptive immunity; base; cell type; cytotoxic; immunogenic; in vivo; insight; killings; melanoma; neoplastic cell; pathogen; protein expression; public health relevance; receptor; recombinase; research study; response; treatment strategy; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Natural Killer (NK) cells are important for the control of viral infections and tumorigenesis. Upon activation, NK cells rapidly produce lytic molecules that are important for killing stressed, transformed, or infected target cells and effector cytokins that further stimulating the immune response. Post activation, these potent immune responses must be tightly regulated to maintain a productive response and rein in cytotoxic cells to avoid autoimmune disease. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) is inhibitory receptor that is an essential modulator of T cell responses. Preliminary data from our lab shows, for the first time, that this important response regulator is expressed on NK cells during viral infection. However, it is unclear how CTLA-4 modulates NK cell responses. Further understanding of the underlying molecular mechanisms of NK cell responses will be useful in adapting and enhancing NK cell-based immunotherapy against cancer and infectious disease. To this end, we aim to elucidate the regulatory role of CTLA-4 on NK cell responses in vivo. Humans specifically lacking NK cells or NK cells effector function are particularly susceptible to human cytomegalovirus (HCMV). Though latent in a majority of the human population, it can cause life-threatening complications in newborns and immunosuppressed patients (e.g. AIDS patients, cancer patients undergoing radiation therapy, and transplant patients treated with immunosuppressive drugs). Using a mouse homolog (MCMV) of this disease, we will test the role of CTLA-4 in viral control by NK cells. Furthermore, we will investigate the role of CTLA-4 in tumor surveillance by NK cells using an established B16 mouse melanoma model, which is susceptible to NK cell eradication. B16 melanoma also mimics the intricacies of human tumor development, progress, and treatment strategies because it does not produce a productive immune response. Manipulation of CTLA-4 within the immune system is an emerging strategy of effective vaccination and tumor therapy. Therefore, understanding how CTLA-4 can modulate NK cell responses against both infectious disease and cancer will aid in future attempts to harness the immune system against these ailments in a clinical setting.

描述（由申请人提供）：自然杀伤（NK）细胞对于控制病毒感染和肿瘤发生很重要。激活后，NK 细胞迅速产生裂解分子，这些分子对于杀死应激、转化或感染的靶细胞和效应细胞因子非常重要，从而进一步刺激免疫反应。激活后，必须严格调节这些有效的免疫反应，以维持有效的反应并控制细胞毒性细胞，以避免自身免疫性疾病。 CTLA-4（细胞毒性 T 淋巴细胞抗原 4）是抑制性受体，是 T 细胞反应的重要调节剂。我们实验室的初步数据首次表明，这种重要的反应调节因子在病毒感染期间在 NK 细胞上表达。然而，尚不清楚 CTLA-4 如何调节 NK 细胞反应。进一步了解 NK 细胞反应的潜在分子机制将有助于适应和增强基于 NK 细胞的针对癌症和传染病的免疫疗法。为此，我们旨在阐明 CTLA-4 对体内 NK 细胞反应的调节作用。特别缺乏 NK 细胞或 NK 细胞效应功能的人类特别容易受到人巨细胞病毒 (HCMV) 的影响。尽管它在大多数人群中是潜伏的，但它可能会导致新生儿和免疫抑制患者（例如艾滋病患者、接受放射治疗的癌症患者以及接受免疫抑制药物治疗的移植患者）出现危及生命的并发症。使用该疾病的小鼠同系物 (MCMV)，我们将测试 CTLA-4 在 NK 细胞病毒控制中的作用。此外，我们将研究 CTLA-4 在 使用已建立的 B16 小鼠黑色素瘤模型通过 NK 细胞监测肿瘤，该模型容易被 NK 细胞根除。 B16 黑色素瘤还模仿人类肿瘤发展、进展和治疗策略的复杂性，因为它不会产生有效的免疫反应。在免疫系统内操纵 CTLA-4 是有效疫苗接种和肿瘤治疗的新兴策略。因此，了解 CTLA-4 如何调节 NK 细胞针对传染病和癌症的反应将有助于未来在临床环境中利用免疫系统对抗这些疾病。