Combined TLR/CD40-agonist induced CD8+ T cell memory

性状（由申请方提供）：严格控制动物中淋巴细胞的特异性和数量，以避免自身免疫和避免既往感染期间产生的淋巴细胞蓄积。这种控制可以通过选择事件导致自身反应性淋巴细胞死亡来实现。类似地，许多因感染而产生的淋巴细胞在感染因子消失时死亡。淋巴细胞库也受到淋巴细胞改变其抗原受体的能力的影响。例如，由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攻击性受体的基因或通过沉默自身反应性受体的作用来修饰。在针对天然感染的免疫应答的高峰，宿主可以产生病原体特异性T细胞应答，其占宿主总T细胞库的20-50%。我们现在已经确定了一种疫苗接种策略，该策略能够从纯分子疫苗产生类似水平的T细胞扩增，这是先前开发的疫苗策略不可能实现的结果。这些高水平的CD 8 + T细胞扩增可以通过用抗原与Toll样受体（TLR）和CD 40途径两者的激动剂组合接种宿主来实现。我们现在有初步的数据表明，由TLR/CD 40激动剂联合免疫引起的原发性和记忆性CD 8 + T细胞应答与CD 4 + T细胞的存在无关。这与其他免疫技术相反，在其他免疫技术中，记忆性CD 8 + T细胞应答严重依赖于CD 4 + T细胞的存在。在本文提出的研究中，将研究这种免疫可以产生CD 4非依赖性CD 8 + T细胞应答的机制。这些研究将产生至关重要的信息，了解如何有效的细胞免疫，甚至可以在CD 4缺乏症的背景下产生。理解这些机制至关重要，特别是对于CD 4 + T细胞应答存在不确定的疾病，如癌症，或已知不存在和/或缺乏的疾病，如HIV。这些研究将导致开发针对这些疾病的更有效的疫苗，这些疾病的治疗似乎需要细胞免疫的数量和质量，只有TLR/CD 40激动剂联合免疫才能产生。

DESCRIPTION (provided by applicant): The specificities and numbers of lymphocytes in animals are tightly controlled to avoid autoimmunity and to avoid accumulation of lymphocytes generated during previous infections. This control can be achieved through the death of autoreactive lymphocytes as consequence of 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. We now have preliminary data demonstrating that both primary and memory CD8+ T cell responses elicited by combined TLR/CD40-agonist immunization occur independent of the presence of CD4+ T cells. This is in contrast to other immunization techniques in which memory CD8+ T cell responses are critically dependent upon the presence of CD4+ T cells. In the studies proposed here, the mechanism by which this immunization can generate CD4 independent CD8+ T cell responses will be investigated. These studies will yield information vital to the understanding of how potent cellular immunity can be generated even in the context of CD4 deficiency. Understanding these mechanisms is of critical importance, particularly for disease conditions where the existence of CD4+ T cell response is uncertain, such as in cancer, or is known to be absent and/or deficient, such as in HIV. These studies will lead to the development of more potent vaccines against these kinds of diseases whose treatment seems to require the quantity and quality of cellular immunity that only combined TLR/CD40-agonist immunization is capable of generating.