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

描述(由申请人提供)：本研究旨在确定体内和体外产生CD4细胞毒性T淋巴细胞或CD4CTL的条件和因素，并确定体内CD4CTL在抗病毒免疫和免疫诱导的病理中的直接作用。许多病毒会持续感染，这些感染大多是无害的。然而，对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，而在缺乏免疫保护的情况下，如免疫受损的人，病毒的重新激活往往会导致致命的疾病。目前尚不清楚哪些免疫细胞控制了持久性病毒或导致了免疫病理，但细胞溶解的cd4效应细胞与慢性病毒感染以及 病毒诱导的自身免疫。然而，CD4CTL的直接作用尚未确定，其在健康和疾病中的具体作用仍未被探索。最近，我们发表了一项研究，表明CD4CTL形成了一个独立的效应亚群，有别于任何CD4T辅助细胞亚型。我们进一步确定，CD4CTL是传统的天然CD4T细胞的后代，这些CD4T细胞对慢性抗原刺激(如慢性病毒感染)做出功能性重新编程，并成为MHC II类限制性CTL。结合这些深刻的新见解以及复杂的功能获得和丧失方法，我们建议在这里测试这一假设，即CD4CTL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。

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.