Role of CXCR4 in immunoglobulin light chain recombination

CXCR4在免疫球蛋白轻链重组中的作用

• 批准号: 10117864
• 负责人: Marcus Ramsay Clark
• 金额: $ 57.96万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117864
• 关键词: Antigens; Applications Grants; B cell repertoire; B-Cell Development; B-Lymphocytes; Biological; Biological Process; Bone Marrow; CXCR4 Receptors; CXCR4 gene; Cell Cycle; Cell Proliferation; Cells; Complex; Data; Development; Ensure; Failure; Genes; Genetic Recombination; Genomic Instability; Humoral Immunities; IGH@ gene cluster; IL7 gene; IRF4 gene; IgK; Immune response; Immunity; Immunoglobulin Gene Rearrangement; Immunoglobulin Genes; Immunoglobulin Light Chain Genes; Immunologics; Immunology; In Vitro; Infection; Instruction; Interleukin 7 Receptor; Light; Light-Chain Immunoglobulins; Lymphopoiesis; Malignant Neoplasms; Mediating; Modeling; Molecular; Peripheral; Play; Positioning Attribute; Process; Proliferating; Repression; Risk; Role; Self Tolerance; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; TCF3 gene; Testing; Time; Work; autoreactivity; central tolerance; chemokine; chemokine receptor; experimental study; human disease; leukemic transformation; novel; progenitor; programs; receptor; role model; surrogate light chain

PROJECT SUMMARY In B lymphopoiesis there are alternating and mutually exclusive state of stochastic immunoglobulin gene recombination and cell proliferation with selection. Following successful rearrangement of the Ig heavy chain gene, Igµ pairs with surrogate light chain (SLC) to form the pre-BCR, expression of which is associated with clonal large pre-B cell expansion. However, at the subsequent developmental stage, small pre-B cells must fully exit cell cycle before initiating Ig light chain (IgL) gene recombination. Failure to do so risks genomic instability and leukemic transformation. Work from our lab and others has demonstrated that the IL-7R drives proliferation while the pre-BCR primarily appears tasked with IgL recombination. However, there is an apparent paradox in that IgL rearrangement occurs in small pre-B cells in which there is concurrent strong repression of SLC. There are two possibilities. The pre-BCR could initiate a complex developmental program in large pre-B cells that is executed in small pre-B cells. Alternatively, there could be other receptors or mechanisms that orchestrate IgL chain recombination. We now demonstrate that CXCR4, which is upregulated in small pre-B cells, directly transmits signals that open Igk to recombination. Indeed, it is CXCR4-mediated ERK activation, and not escape from IL-7, nor expression of the pre-BCR, that mediates late B lymphopoiesis. These and other data suggest a new model of B lymphopoiesis in which sequential signaling through three receptors, the IL-7R, pre-BCR and CXCR4, orchestrate critical cell fate decisions. We propose to test this mode in the following Specific Aims: Aim 1. Identify the signaling pathways specifically downstream of the pre-BCR. Aim 2: Determine how CXCR4 signals integrate with pre-BCR/IL-7Resc to drive Igk recombination. Aim 3. Determine how CXCR4 regulates receptor editing.

项目摘要 在B淋巴细胞中，随机免疫球蛋白基因有替代性和相互排斥的状态 重组和细胞增殖与选择。成功重新排列IG重链之后 基因，与替代光链（SLC）的Igµ对形成前BCR，其表达与 克隆大型前B细胞扩张。但是，在随后的发育阶段，小的前B细胞必须完全 启动IG轻链（IGL）基因重组之前退出细胞周期。不这样做会冒着基因组不稳定性的风险 和白血病转变。我们实验室和其他人的工作表明，IL-7R驱动了扩散 虽然前BCR的主要是IGL重组的任务。但是，有一个外观悖论 IgL重排发生在SLC的同时强烈表示的小型前B细胞中。那里 是两种可能性。前BCR可以在大型前B细胞中启动复杂的发展程序，这是 在小型B细胞中执行。另外，可能还有其他受体或机制来编排IGL 链重组。现在，我们证明了在小型B细胞中更新的CXCR4，直接 传输打开IGK重组的信号。确实，它是CXCR4介导的ERK激活，而不是逃脱 从IL-7，也没有表达BCR的表达，介导了晚期淋巴细胞。这些数据和其他数据表明 B淋巴细胞的新模型，其中通过三个受体IL-7R，PRE-BCR和 CXCR4，编排关键细胞脂肪决策。我们建议在以下特定目标中测试此模式： AIM 1。确定特定于BCR下游的信号通路。 AIM 2：确定CXCR4信号如何与前BCR/IL-7Resc集成以驱动IGK重组。 目标3。确定CXCR4如何调节受体编辑。