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: 10569055
• 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/10569055
• 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; Evaluation; 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; 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; antagonist; autoreactivity; central tolerance; chemokine; chemokine receptor; experimental study; human disease; leukemic transformation; novel; progenitor; programs; receptor; role model; surrogate light chain; transmission process

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.

项目概要 在B淋巴细胞生成过程中，随机免疫球蛋白基因存在交替且相互排斥的状态 Ig 重链成功重排后的重组和细胞增殖。 Igμ 基因与替代轻链 (SLC) 配对形成前 BCR，其表达与 然而，在随后的发育阶段，小前B细胞必须充分克隆。 在启动 Ig 轻链 (IgL) 基因重组之前退出细胞周期，否则基因组将面临不稳定的风险。 我们实验室和其他实验室的工作表明，IL-7R 可促进增殖。 虽然前 BCR 主要负责 IgL 重组，但存在明显的悖论。 IgL 重排发生在小前 B 细胞中，其中同时存在 SLC 的强烈抑制。 有两种可能性。前 BCR 可以在大前 B 细胞中启动复杂的发育程序。 或者，可能还有其他受体或机制来协调 IgL。 我们现在证明 CXCR4 在小前 B 细胞中直接上调。 事实上，它是 CXCR4 介导的 ERK 激活，而不是逃逸。 来自 IL-7 或前 BCR 的表达，介导晚期 B 淋巴细胞生成。这些和其他数据表明。 B 淋巴细胞生成的新模型，其中通过三种受体（IL-7R、前 BCR 和 CXCR4，协调关键的细胞命运决策，我们建议在以下具体目标中测试此模式： 目标 1. 确定前 BCR 下游的信号通路。 目标 2：确定 CXCR4 信号如何与前 BCR/IL-7Resc 整合以驱动 Igk 重组。 目标 3. 确定 CXCR4 如何调节受体编辑。