STRUCTURAL/FUNCTION B CELL DIFFERENTIATION ANTIGENS

根据B细胞的不同阶段，CD40可以a)将细胞从细胞中拯救出来 死亡，b)刺激细胞生存，c)使细胞变得敏感或 抵抗细胞死亡，或d)诱导细胞死亡。的主要目标是 这项提议是定义信令通过的机制 CD40促进细胞存活或死亡。我们将从定义 CD40诱导存活的B细胞系中的CD40信号通路与。 死亡，然后我们将探索CD40的下游元件是如何 调节小鼠未成熟和人类记忆B细胞命运的途径 生发中心(GC)B细胞和记忆B细胞，以及人树突状细胞 (分布式控制系统)。我们的具体目标是：1)检验不同的假设 核因子-kappaB等下游蛋白功能决定CD40 诱导生存或抑制信号。我们将比较这些信号 CD40将细胞从死亡中拯救出来的途径与CD40诱导的途径 导致死亡表型。我们将测试CD40诱导的生长停滞 而死亡可以通过生存/抗凋亡基因，如cIAP2， Bc1-X和/或A1；2)验证抗凋亡的bc l-2 家族成员Al对CD40拯救未成熟B细胞是必不可少的 避免死亡；b)诱导和维持记忆B细胞。我们发现 编码Bcl2家族成员A1的mRNA在人胃癌和胃癌中表达 记忆B细胞，与GC B细胞表面CD40的结合增加 Al的表达。因此，Al可能在调节中起关键作用 通过CD40决定B细胞的命运。因此，我们将使用A1-/-小鼠测试 假设Al-/-B细胞不能通过CD40信号传递到 增殖或从细胞死亡中解救出来。我们还将测试A1-/- 小鼠有缺陷的CD40依赖的记忆B细胞反应；3) GC和记忆B细胞的产生涉及到精细的选择 流程。在目标3中，我们将研究CD40和CD40如何调节 受体CDw150(SLAM)表达于GC B细胞和/或记忆B细胞， 影响细胞命运，包括Fas介导的细胞死亡。特别是，我们 将检验CDw150功能调节寿命的假设 4)CD40既可诱导DC存活，又可将其置于 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， 我们将验证CD40可以诱导树突状细胞 更容易受到细胞死亡的影响。这些研究应该会带来新的 对CD40如何调节GC形成和B细胞记忆的洞察。

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.