IFNalphaBeta-Dependent and-Independent TLR/CD40 Synergy

严格控制动物体内淋巴细胞的特异性和数量，以避免自身免疫和避免在免疫过程中产生的淋巴细胞积聚。 以前的感染。这种控制可以通过自身反应性淋巴细胞的死亡来实现，这是选择事件的结果。同样，许多淋巴细胞 当感染因子消失时，这些因感染而产生的细胞就会死亡。淋巴细胞库也受到淋巴细胞的能力的影响， 改变它们的抗原受体例如，一些自身反应性淋巴细胞表达的抗原受体可以通过缺失编码 或通过抑制自身反应性受体的作用。 在针对自然感染的免疫应答的高峰期，宿主可以产生病原体特异性T细胞， 这些应答占宿主总T细胞库的20-50%。我们现在已经确定了一种疫苗 一种能够从纯分子疫苗产生类似水平的T细胞扩增的策略， 这是以前开发的疫苗策略无法实现的结果。这些高水平的CD 8 + T细胞扩增 可以通过用抗原与Toll样蛋白和Toll样蛋白的激动剂的组合接种宿主来实现 受体（TLR）和CD 40通路（TLR/CD 40激动剂联合免疫）。我们进一步 鉴定了1型干扰素（IFNap）作为这种协同作用的中心介质，其响应于某些TLR/CD 40- 激动剂组合。由于IFNap通常与病毒复制的抑制有关，而不是 促进CD 8 + T细胞扩增，这些研究已经确定了IFNap在CD 8 + T细胞增殖中的潜在新作用。 促进适应性免疫。最近，我们已经观察到调节性CD 4细胞和树突状细胞都可以被激活。 细胞表达TNF配体超家族成员是IFNap影响的关键成分 CD 8 + T细胞免疫。在这里提出的研究中，IFNap促进CD 8 + T细胞增殖的机制是： TLR/CD 40激动剂联合免疫后的细胞扩增和长期保护性免疫将 被确定。了解这些机制自然会导致开发更有效的 针对艾滋病毒、丙型肝炎病毒和癌症等疾病的疫苗;治疗似乎需要 在某些实施方案中，TLR/CD 40激动剂免疫能够产生仅组合的TLR/CD 40激动剂免疫能够产生的细胞免疫的量级。

The specificities and numbers of lymphocytes in animals are tightly controlled to avoid autoimmunity and to avoid accumulation of lymphocytesgeneratedduring previous infections. This control can be achieved through the death of autoreactive lymphocytes as consequenceof selection events. Similarly, many lymphocytes that are generated in response to infections die when the infectious agent disappears. The lymphocyte repertoire is also influenced by the ability of lymphocytes to alter their antigen receptor. For example, the antigen receptor expressed by some autoreactive lymphocytes can be modified either by deletion of the genes encoding the offending receptor, or by silencing the action of the autoreactive receptor. At the peak of an immune response against a natural infection, a host can generate pathogen-specific T cell responses that comprise 20-50% of the hosts' total T cell pool. We have now identified a vaccination strategy that is able to generate a similar level of T cell expansion from a purely molecular based vaccine, a result not possible with previously developed vaccine strategies. These high levels of CD8+ T cell expansion can be achieved by the vaccination of a host with antigen in combination with agonists for both the Toll-Like Receptor (TLR) and CD40 pathways (combined TLR/CD40-agonist immunization). We have further identified Type 1 interferon (IFNap) as a central mediator of this synergy in response to certain TLR/CD40- agonist combinations. As IFNap is more often associated with inhibition of virus replication rather than promotion of CD8+ T cell expansion, these studies have identified a potentially novel role for IFNap in promoting adaptive immunity. Most recently, we have observed that both regulatory CD4 cells and dendritic cells expression of TNF ligand superfamily members are critical components by which IFNap influences CD8+ T cell immunity. In the studies proposed here, the mechanism(s) by which IFNap promotes CD8+ T cell expansion and long term protective immunity following combined TLR/CD40-agonist immunization will be determined. Understanding these mechanisms will naturally lead to the development of more potent vaccines against diseases such as HIV, HCV and cancer; diseases whose treatment seems to require the magnitude of cellular immunity that only combined TLR/CD40-agonist immunization is capable of generating.