B cell zone reticular cell microenvironments shape CXCL13 gradient formation

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

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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