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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.


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, Mark C Coles. B cell zone reticular cell microenvironments shape CXCL13 gradient formation. Nature communications. 2020 Jul 22;11(1):3677

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PMID: 32699279

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