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

描述(申请人提供)：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，并避免在先前感染期间产生的淋巴细胞积累。这种控制可以通过选择事件导致的自身反应淋巴细胞的死亡来实现。同样，许多为应对感染而产生的淋巴细胞在感染剂消失时死亡。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，一些自体反应性淋巴细胞表达的抗原受体可以通过删除编码有害受体的基因或通过沉默自体反应性受体的作用来修饰。在针对自然感染的免疫反应的高峰期，宿主可以产生病原体特异性T细胞反应，占宿主总T细胞池的20%-50%。我们现在已经确定了一种疫苗策略，它能够从纯分子疫苗中产生类似水平的T细胞增殖，这是以前开发的疫苗策略不可能实现的结果。这种高水平的CD8+T细胞扩增可以通过接种宿主抗原和Toll样受体(TLR)和CD40途径的激动剂来实现。我们现在有初步数据表明，由TLR/CD40激动剂联合免疫所引发的初级和记忆性CD8+T细胞反应不依赖于CD4+T细胞的存在。这与其他免疫技术不同，在其他免疫技术中，记忆CD8+T细胞的反应严重依赖于CD4+T细胞的存在。在这里提出的研究中，这种免疫可以产生非依赖于CD4的CD8+T细胞反应的机制将被研究。这些研究将提供至关重要的信息，以了解即使在CD4缺乏的情况下，如何产生强大的细胞免疫。了解这些机制是至关重要的，特别是对于疾病条件下，CD4+T细胞反应的存在是不确定的，如癌症，或已知缺失和/或缺陷，如艾滋病毒。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只有结合TLR/CD40激动剂免疫才能产生的细胞免疫的数量和质量。

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.