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CD4 CTL的条件和因素，以及确定体内CD4 CTL在抗病毒免疫和免疫诱导病理中的直接作用。许多病毒建立持续感染，这大多是无害的。然而，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，如在免疫受损的个体中，病毒的再活化经常导致致命疾病。尚不清楚哪些免疫细胞使持久性病毒处于控制之下或引起免疫病理学，但溶细胞性CD4效应细胞与慢性病毒感染以及免疫性疾病相关。 病毒引起的自身免疫然而，CD4 CTL的直接作用尚未确定，它们在健康和疾病中的具体作用仍有待研究。最近，我们发表了一项研究表明，CD4 CTL形成一个独立的效应子亚群，不同于任何CD4辅助性T细胞亚型。我们进一步确定，CD4 CTL是传统的幼稚CD4 T细胞的后代，这些T细胞在慢性抗原刺激（如慢性病毒感染）的反应中进行功能性重编程，并成为MHC II类限制性CTL。使用这些深刻的新见解与复杂的增益和功能丧失的方法相结合，我们建议在这里测试的假设，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会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.