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

描述（由申请方提供）：自然杀伤（NK）细胞对于控制病毒感染和肿瘤发生非常重要。在活化后，NK细胞迅速产生对于杀死应激的、转化的或感染的靶细胞重要的裂解分子和进一步刺激免疫应答的效应细胞因子。激活后，这些有效的免疫反应必须受到严格的调节，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，目前还不清楚CTLA-4如何调节NK细胞应答。对NK细胞应答的潜在分子机制的进一步理解将有助于适应和增强针对癌症和感染性疾病的基于NK细胞的免疫疗法。为此，我们的目的是阐明CTLA-4在体内NK细胞反应的调节作用。特别缺乏NK细胞或NK细胞效应子功能的人对人巨细胞病毒（HCMV）特别敏感。虽然在大多数人群中潜伏，但它可在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和接受免疫抑制药物治疗的移植患者）中引起危及生命的并发症。使用这种疾病的小鼠同源物（MCMV），我们将测试CTLA-4在NK细胞控制病毒中的作用。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细胞进行肿瘤监测，该模型对NK细胞根除敏感。B16黑色素瘤也模仿人类肿瘤发展，进展和治疗策略的复杂性，因为它不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细胞对感染性疾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的尝试。

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.