REGULATION OF LYMPHOCYTE METABOLISM AND HOMEOSTATIS BY THE C-MYC/AP4 AXIS

 描述(由申请人提供)：对病原体的免疫反应需要淋巴细胞协调它们激活的两个暂时不同的阶段。当遇到抗原(Ag)时，B和T细胞启动激活，这是一个涉及基因表达、蛋白质合成和碳水化合物代谢动态增加的程序。在启动阶段之后，必须维持激活程序以完成克隆扩增并产生有效清除病原体所需的数量的抗原特异性淋巴细胞。转录因子cMyc在淋巴细胞活化的起始阶段起着重要作用。然而，我们的数据显示，cMyc的表达并不在T细胞反应的整个时期持续存在。这一结果表明，其他转录因子可能替代cMyc表达的缺失来维持淋巴细胞的增殖。我们发现，在后Myc阶段，cMyc诱导的转录因子AP4是CD8 T淋巴细胞增殖的关键细胞内在调节因子。AP4是许多cMyc靶基因持续转录所必需的，它与假定的调控元件直接结合，是CD8T细胞对病毒感染的保护性免疫所必需的。在这项资助中，我们将研究这两种转录因子在免疫反应中的时间调节要求的生物学意义，免疫反应可能平衡正常的淋巴细胞增殖和防止淋巴肿大。

 DESCRIPTION (provided by applicant): Immune responses to pathogens require lymphocytes to orchestrate two temporally distinct phases of their activation. Upon antigen (Ag) encounter, B and T cells initiate activation, a program involving dynamic increases in gene expression, protein synthesis, and carbohydrate metabolism. Following the initiation phase, activation programs must be maintained to complete clonal expansion and generate the numbers of Ag- specific lymphocytes required for efficient pathogen clearance. The transcription factor cMyc plays an essential role in the initiation phase of lymphocyte activation. However, our data show that cMyc expression does not persist during the entire period of T cell responses. This result suggests that other transcription factors may substitute the loss of cMyc expression to maintain lymphocyte proliferation. We discovered that a cMyc- inducible transcription factor, AP4, is a critical cell-intrinsic regulator of CD8 T lymphocyte proliferation during the post-Myc phase. AP4 is required for continued transcription of many cMyc target genes via its direct binding to presumed regulatory elements and essential for protective immunity by CD8 T cells against viral infection. In this grant, we will study the biological significance of the temporally regulated requirements of the two transcription factors in immune responses that may balance normal lymphocyte proliferation and prevention of lymphomagenesis.