B cell zone reticular cell microenvironments shape CXCL13 gradient formation

Jason Cosgrove, Mario Novkovic, Stefan Albrecht, Natalia B. Pikor, Zhaoukun Zhou, Lucas Onder, Urs Mörbe, Jovana Cupovic, Helen Miller, Kieran Alden, Anne Thuery, Peter O’Toole, Rita Pinter, Simon Jarrett, Emily Taylor, Daniel Venetz, Manfred Heller, Mariagrazia Uguccioni, Daniel F. Legler, Charles J. LaceyAndrew Coatesworth, Wojciech G. Polak, Tom Cupedo, Bénedicte Manoury, Marcus Thelen, Jens V. Stein, Marlene Wolf, Mark C. Leake*, Jon Timmis*, Burkhard Ludewig*, Mark C. Coles*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (SciVal)

Abstract

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients.

Original languageEnglish
Article number3677
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 01 Dec 2020

Keywords

  • Adaptive Immunity
  • Animals
  • B-Lymphocytes/cytology
  • Cathepsin B/genetics
  • Cell Line
  • Cellular Microenvironment/immunology
  • Chemokine CXCL13/immunology
  • Computer Simulation
  • Dendritic Cells, Follicular/cytology
  • Extracellular Matrix/metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Biological
  • Palatine Tonsil/cytology
  • Recombinant Proteins/genetics
  • Stromal Cells/immunology

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