B cell zone reticular cell microenvironments shape CXCL13 gradient formation.

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; ... (2020). B cell zone reticular cell microenvironments shape CXCL13 gradient formation. Nature Communications, 11(1), p. 3677. Springer Nature 10.1038/s41467-020-17135-2

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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.

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