Deciphering CD8 Dendritic Cell Development for the Improvement of Vaccine

描述(由申请人提供)：病毒感染和癌症是将从治疗性疫苗的改进中极大受益的疾病的例子。许多类型的此类疾病缺乏有效的治疗方法，这使得开发这类疫苗成为优先事项，正在进行的大量临床试验证明，疫苗的研制是一个引起积极兴趣的领域。在疫苗开发和设计领域，取得的主要成果是 有效地诱导体液免疫反应。然而，使用疫苗根除癌症和一些病原体将需要产生强大的细胞介导的免疫，特别是CD8T细胞反应。目前，许多临床试验正在试图开发针对癌症的治疗性疫苗，一个共同的感兴趣的过程是将有效的抗原递呈给T细胞。自然，树突状细胞因其出色的抗原提呈能力而成为疫苗设计的重要组成部分。尤其是，CD8常规树突状细胞(CDC)在这一过程中起着至关重要的作用，因为它们在交叉递呈中起着关键作用，并且具有诱导细胞毒性T淋巴细胞效应活性和记忆形成的强大能力。然而，尽管它们很重要，但这些细胞的发育机制尚不清楚，这限制了我们有选择地扩大CD8 CDC群体的能力。然而，我们实验室的最新发现正在帮助我们理解这一过程。我们已经确定了小鼠品系之间的遗传背景差异，这将为我们提供必要的工具来识别CD8 CDC承诺的祖细胞。反过来，我们将能够对具有不同CDC发育潜力的祖细胞进行新的遗传图谱和比较，以确定负责CDC两个分支发育的转录因子电路。此前我们的实验室显示，BATF3-/-小鼠缺乏CD8 CDC。有趣的是，我们在IRF8的启动子中发现了一个依赖于BATF3的IRF8结合顺式元件，IRF8是CD8 CDC发育的关键转录因子。因此，我们的目的是测试CD8 CDC的IRF8表达维持是否依赖于这种顺式元件中的IRF8-BATF3复合体结合。这些发现将有助于我们理解CDC的分化机制，从而开发CD8 CDC的治疗性靶向扩增，以改进疫苗设计。

DESCRIPTION (provided by applicant): Viral infections and cancer are examples of diseases that would greatly benefit from the improvement of therapeutic vaccines. The lack of effective treatments for many types of these diseases makes the development of such vaccines a priority and its elaboration is an area of active interest as evidenced by the great number of ongoing clinical trials. In the realm of vaccine development and design, the primary achieved effect is the potent induction of humoral immune responses. However, the use of vaccines to eradicate cancers and some pathogens will require the generation of robust cell-mediated immunity, particularly CD8 T-cell responses. Currently, numerous clinical trials are trying to develop therapeutic vaccinations against cancer and a common process of interest is the efficient antigen presentation to T cells. Naturally, dendritic cells have become an important component of vaccine design due to their excellent antigen presentation capacity. In particular, CD8 conventional dendritic cells (cDCs) are of the utmost importance in this process due to their critical role in cross-presentation and their potent ability to induce cytotoxic T-lymphocyte effector activity and memory formation. Nevertheless, in spite of their importance, the mechanism by which these cells develop is unknown, limiting our capacity to selectively expand the CD8 cDC population. However, recent findings in our laboratory are helping us to understand this process. We have identified genetic background differences amongst mouse strains that will provide us with the necessary tools for the identification of a CD8 cDC committed progenitor. In turn, we will be able to perform a novel genetic profiling and comparison of progenitors with different cDC developmental potential in order to identify the transcription factor circuitry responsible for the development of both branches of cDCs. Previously our laboratory showed that the Batf3-/- mice lack CD8 cDCs. Interestingly, we have identified a Batf3-dependent Irf8 binding cis-element in the promoter of Irf8, a critical transcription factor for the development of CD8 cDCs. Thus, we aim to test if the Irf8 expression maintenance of the CD8 cDCs depends on the Irf8-Batf3 complex binding in such cis-element. Such discoveries will help us understand the cDC differentiation mechanism so that therapeutic targeted expansion of CD8 cDCs can be developed for the improvement of vaccine design.