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.

项目总结