DIFFERENTIATION AND ANTI-VIRAL PROTECTIVE AND PATHOGENIC ROLES OF CD4 CTL

CD4 CTL 的分化、抗病毒保护和致病作用

基本信息

批准号：
8655464
负责人：
HILDE MC CHEROUTRE
金额：
$ 44.25万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-07 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655464
关键词：
Acquired Immunodeficiency Syndrome Acute Address Antigens Antiviral Agents Autoimmune Process Autoimmunity Biology CD4 Positive T Lymphocytes Cells Characteristics Chronic Cytokine Network Pathway Cytomegalovirus Cytotoxic T-Lymphocytes Data Disease Effector Cell Evaluation Event Gene Expression Generations Genes Genetic Transcription Government Health Hypersensitivity Immune Immune response Immunity Immunology In Vitro Individual Infection Inflammatory Institutes Knowledge Lead Link MHC Class II Genes Malignant Neoplasms Mediating Mission Molecular Mouse Strains Mus Pathology Persons Play Positioning Attribute Process Publishing Regulation Research Role System Testing Th1 Cells Time Transplant Recipients United States National Institutes of Health Vaccines Variant Viral Virus Virus Diseases base cell type combat cytokine design gain of function in vivo insight loss of function mortality novel prevent programs public health relevance response tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The study here sets out to define the conditions and factors involved in the in vivo and in vitro generation of CD4 cytotoxic T lymphocytes or CD4 CTL, in addition to determining the direct roles for CD4 CTL in vivo in antiviral immunity and immune-induced pathology. Many viruses establish persistent infections, which are mostly innocuous. However, immune control of these chronic viral infections has also been linked with viral-induced autoimmunity whereas in the absence of immune protection as in immune compromised individuals, reactivation of the viruses frequently causes lethal diseases. It is not known which immune cells keep persistent viruses under control or cause immune pathology, but cytolytic CD4 effector cells have been associated with chronic viral infections as well as with viral- induced autoimmunity. However, a direct role for CD4 CTL has not been determined and their specific contributions in health and disease remain unexplored. Recently, we published a study showing that CD4 CTL form a separate effector subset distinct from any CD4 T-helper subtype. We further determined that CD4 CTL are progeny of conventional na¿ve CD4 T cells that functionally reprogram in response to chronic antigen-stimulation such as chronic viral infections, and become MHC class II-restricted CTL. Using a combination of these profound new insights together with sophisticated gain- and loss-of-function approaches, we propose here to test the hypothesis that CD4 CTL play critical roles in controlling chronic viral infection and furthermore, that aberrant regulation of these cells might lead to viral-induced immune pathology and autoimmunity.

描述（由申请人提供）：除了确定 CD4 CTL 体内抗病毒的直接作用外，本研究还旨在定义体内和体外生成 CD4 细胞毒性 T 淋巴细胞或 CD4 CTL 所涉及的条件和因素。许多病毒会造成持续性感染，这些感染大多是无害的，然而，在缺乏免疫保护的情况下，这些慢性病毒感染的免疫控制也与病毒诱导的自身免疫有关。对于个体来说，病毒的重新激活经常会导致致命的疾病，目前尚不清楚哪些免疫细胞能够控制持续存在的病毒或引起免疫病理，但溶细胞性 CD4 效应细胞与慢性病毒感染以及病毒感染有关。然而，CD4 CTL 的直接作用尚未确定，并且其在健康和疾病中的具体贡献仍未被探索。最近，我们发表的一项研究表明，CD4 CTL 形成了一个不同于任何 CD4 T 辅助细胞的独立效应子集。我们进一步确定 CD4 CTL 是传统 na¿ 的后代。将这些深刻的新见解与复杂的功能获得和丧失方法相结合，可以对慢性抗原刺激（例如慢性病毒感染）进行功能性重编程，并成为 MHC II 类限制性 CTL。我们在此提出检验以下假设：CD4 CTL 在控制慢性病毒感染中发挥关键作用，此外，这些细胞的异常调节可能导致病毒诱导的免疫病理和自身免疫。