Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

• 成果类型: Article
• 署名作者: Narayanan, Haripriya Vaidehi; Xiang, Mark Y.; Chen, Yijia; Huang, Helen; Roy, Sukanya; Makkar, Himani; Hoffmann, Alexander; Roy, Koushik
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Utah System of Higher Education; University of Utah
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8601
• DOI: 10.1073/pnas.2309686121
• 发表日期: 2024-07-23
• 关键词: negative feedback; fold-change; gene; transcription; variability; rel; Heterogeneity; Robustness; origins; epsilon

摘要

Antibody responses require the proliferative expansion of B cells controlled by affinity- dependent signals. Yet, proliferative bursts are heterogeneous, varying between 0 and 8 divisions in response to the same stimulus. NF kappa B cRel is activated in response to immune stimulation in B cells and is genetically required for proliferation. Here, we asked whether proliferative heterogeneity is controlled by natural variations in cRel abundance. We developed a fluorescent reporter mTFP1- cRel for the direct observation of cRel in live proliferating B cells. We found that cRel is heterogeneously distributed among na & iuml;ve B cells, which are enriched for high expressors in a heavy- tailed distribution. We found that high cRel expressors show faster activation of the proliferative program, but do not sustain it well, with population expansion decaying earlier. With a mathematical model of the molecular network, we showed that cRel heterogeneity arises from balancing positive feedback by autoregulation and negative feedback by its inhibitor I kappa B epsilon, confirmed by mouse knockouts. Using live- cell fluorescence microscopy, we showed that increased cRel primes B cells for early proliferation via higher basal expression of the cell cycle driver cMyc. However, peak cMyc induction amplitude is constrained by incoherent feedforward regulation, decoding the fold change of cRel activity to terminate the proliferative burst. This results in a complex nonlinear, nonmonotonic relationship between cRel expression and the extent of complement gene knockout results and to learn about quantitative relationships between biological processes and their key regulators in the context of natural variations.