STRUCTURAL/FUNCTION B CELL DIFFERENTIATION ANTIGENS

根据B细胞的阶段，CD 40可以a）从细胞中拯救细胞， 死亡，B）刺激细胞存活，c）使细胞易感或 抵抗细胞死亡，或d）诱导细胞死亡。 的主要目标 该提议是定义通过其发送信号的机制， CD 40促进细胞存活或死亡。 我们将首先定义 CD 40诱导存活的B细胞系中的CD 40信号传导途径与 死亡，然后我们将探索CD 40中的下游元件如何 途径调节小鼠未成熟和记忆B细胞的命运，人类 生发中心（GC）B和记忆B细胞，以及人树突状细胞 （发展中国家）。 我们的具体目标是：1）检验不同的假设， 下游蛋白如NF-κ B的功能是决定CD 40 诱导存活或抑制信号。 我们将比较信号 诱导的途径，其中CD 40拯救细胞免于死亡，而CD 40 诱导死亡表型。 我们将测试CD 40诱导的生长停滞是否 并且死亡可以通过存活/抗凋亡基因如cIAP 2来预防， Bcl-X和/或A1; 2）验证抗凋亡Bcl-2 家族成员Al对于CD 40是必需的，以a）拯救未成熟的B细胞 和B）诱导和维持记忆B细胞。 我们发现 编码Bcl-2家族成员A1的mRNA在人GC中表达， 记忆B细胞，并且在GC B细胞上连接CD 40增加 因此，Al可能在调节细胞的生长中起关键作用。 B细胞的命运。 因此，使用A1-/-小鼠，我们将测试 假设Al -/- B细胞不能通过CD 40信号传导， 增殖或从细胞死亡中拯救出来。我们还将测试A1-/- 小鼠具有缺陷的CD 40依赖性记忆B细胞应答; 3） GC和记忆B细胞的产生涉及精细的选择 流程. 在目标3中，我们将研究CD 40和CD 40调节的 受体，在GC B细胞和/或记忆B细胞上表达的CDw 150（SLAM）， 影响细胞命运，包括Fas介导的细胞死亡。 我们尤其 将测试CDw 150功能调节寿命的假设， 记忆B细胞; 4）CD 40可以诱导DCS的存活，将它们置于 冒着死亡的危险，或者把他们变成杀手。 使用目标3中的方法， 我们将测试CD 40可以诱导树突状细胞的假设 变得更容易受到细胞死亡的影响。 这些研究将带来新的 深入了解CD 40如何调节GC形成和B细胞记忆。

Depending on the stage of a B cell, CD40 can a) rescue cells from cell death, b) stimulate cell survival, c) make cells susceptible or resistant to cell death, or d) induce cell death. The major goal of this proposal is to define the mechanisms by which signaling through CD40 promotes cell survival or death. We will start by defining the CD40 signaling pathways in B cell lines where CD40 induces survival vs. death, and then we will explore how downstream elements in the CD40 pathway regulate the fate of mouse immature and memory B cells, human germinal center (GC) B and memory B cells, and human dendritic cells (DCs). Our specific Aims are: 1) To test the hypothesis that distinct downstream proteins such as NF-kappaB function to determine whether CD40 induces a survival or inhibitory signal. We will compare the signaling pathways induced where CD40 rescues cells from death vs. where CD40 induces death phenotypes. We will test if CD40-induced growth arrest and death can be prevented by survival/anti-apoptotic genes such cIAP2, Bcl-X and/or A1; 2) To test the hypotheses that the anti-apoptotic Bcl-2 family member, Al, is essential for CD40 to a) rescue immature B cells from death and b) to induce and maintain memory B cells. We found that mRNA encoding the Bcl-2 family member, Al, is expressed in human GC and memory B cells, and that ligating CD40 on GC B cells increases expression of Al. Thus, Al may have a critical role in the regulation of B cell fate via CD40. Therefore, using A1-/-mice we will test the hypothesis that Al -/- B cells cannot be signaled via CD40 to proliferate or be rescued from cell death. We will also test if A1-/- mice have defective CD40-dependent memory B cell responses; 3) The generation of GCs and memory B cells involves finely tuned selection processes. In Aim 3 we will examine how CD40 and a CD40-regulated receptor, CDw150 (SLAM) expressed on GC B cells and/or memory B cells, affect cell fate including Fas-mediated cell death. In particular, we will test the hypothesis that CDw150 functions to regulate lifespan of memory B cells; 4) CD40 may either induce survival of DCS, put them at risk to die, or turn them into killers. Using approaches as in Aim 3, we will test the hypothesis that CD40 can induce dendritic cells to become more susceptible to cell death. These studies should lead to new insights into how CD40 regulates GC formation and B cell memory.