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. Lacey, Andrew Coatesworth, Wojciech G. Polak, Tom Cupedo, Bénedicte Manoury, Marcus Thelen, Jens V. Stein, Marlene Wolf, Mark C. Leake (), Jon Timmis (), Burkhard Ludewig () and Mark C. Coles ()
Additional contact information
Jason Cosgrove: University of York
Mario Novkovic: Kantonsspital St. Gallen
Stefan Albrecht: University of Bern
Natalia B. Pikor: Kantonsspital St. Gallen
Zhaoukun Zhou: University of York
Lucas Onder: Kantonsspital St. Gallen
Urs Mörbe: Kantonsspital St. Gallen
Jovana Cupovic: Kantonsspital St. Gallen
Helen Miller: University of York
Kieran Alden: University of York
Anne Thuery: University of York
Peter O’Toole: University of York
Rita Pinter: Kennedy Institute of Rheumatology at the University of Oxford
Simon Jarrett: Kennedy Institute of Rheumatology at the University of Oxford
Emily Taylor: University of York
Daniel Venetz: Università della Svizzera italiana
Manfred Heller: University of Bern
Mariagrazia Uguccioni: Università della Svizzera italiana
Daniel F. Legler: Biotechnology Institute Thurgau (BITg) at the University of Konstanz
Charles J. Lacey: University of York
Andrew Coatesworth: York Teaching Hospital NHS Foundation Trust
Wojciech G. Polak: Erasmus University Medical Centre
Tom Cupedo: Erasmus University Medical Centre
Bénedicte Manoury: France Université René Descartes
Marcus Thelen: Università della Svizzera italiana
Jens V. Stein: University of Fribourg
Marlene Wolf: University of Bern
Mark C. Leake: University of York
Jon Timmis: University of York
Burkhard Ludewig: Kantonsspital St. Gallen
Mark C. Coles: University of York

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17135-2

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