B cell zone reticular cell microenvironments shape CXCL13 gradient formation
Jason Cosgrove, Mario Novković, Stefan Albrecht, Natalia 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 Lacey, A. P. Coatesworth, Wojciech G. Polak, Tom Cupedo, Bénédicte Manoury, Marcus Thelen, Jens V. Stein, Marlene Wolf, Mark C. Leake, Jon Timmis, Burkhard Ludewig, Mark Coles
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.