The role of autophagy in T cell immune response

描述（由申请人提供）：自噬是一种进化上保守的细胞自我消化过程，主要用于在饥饿期间维持细胞能量稳态。近年来，越来越多的证据表明，这一过程与发育和分化、细胞凋亡、癌症、衰老和免疫反应有关。在这项提议中，我们将利用几株转基因小鼠来了解自噬在T细胞介导的免疫反应中的作用。一组小鼠将通过流式细胞术和生化分析，在正常条件下和抗原免疫后，研究不同免疫细胞（如淋巴细胞、巨噬细胞和树突状细胞）自噬活性的诱导。这组小鼠含有几种转基因菌株，表达不同自噬蛋白的绿色荧光蛋白标记版本，如Beclin 1， LC3和Atg5。这些报告小鼠将使我们能够确定免疫细胞中的构成性和抗原诱导的自噬。为了确定自噬在T细胞免疫应答中的功能，我们将使用缺乏自噬必需蛋白Atg7的小鼠。这些小鼠将被免疫，并在没有自噬的情况下使用流式细胞术和功能测定分析T细胞对抗原的免疫反应。这种方法应该为自噬在适应性免疫系统中的作用提供新的见解。

DESCRIPTION (provided by applicant): Autophagy is an evolutionarily conserved process of cellular self-digestion, primarily used to maintain cellular energy homeostasis during starvation. In recent years, the new evidence is emerging implicating this process in development and differentiation, apoptosis, cancer, aging and senescence, and the immune response. In this proposal, we will utilize several strains of genetically modified mice to understand the role of autophagy in the T cell-mediated immune response. One group of mice will be used to study the induction of autophagic activity in different immune cells, such as lymphocytes, macrophages, and dendritic cells, under normal conditions and following immunization with an antigen by flow cytometry and biochemical assays. This group of mice contains several trangenic strains expressing green fluorescence protein-tagged versions of different autophagic proteins, such as Beclin 1, LC3, and Atg5. These reporter mice will allow us to determine a constitutive as well as antigen-induced autophagy in immune cells. To determine the function of autophagy in the T cell immune response, we will use mice deficient in autophagy essential protein Atg7. These mice will be immunized, and the T cell immune response to antigen in the absence of autophagy analyzed using flow cytometry and fuctional assays. This approach should provide a novel insight into the role of autophagy in the adaptive immune system. PUBLIC HEALTH RELEVANCE: In this proposal, we will characterize the role of autophagy in the adaptive immune system. This study should improve our understanding of the adaptive immunity, as well as of the role of autophagy in the initiation of the T cell immune activation and T cell memory, which are essential for the body's defense against different pathogens.