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B cell zone reticular cell microenvironments shape CXCL13 gradient formation

Jason Cosgrove, Mario Novkovic, 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 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

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.
   
citation Cosgrove J, Novkovic M, Albrecht S, Pikor N, Zhou Z, Onder L, Mörbe U, Cupovic J, Miller H, Alden K, Thuery A, O'Toole P, Pinter R, Jarrett S, Taylor E, Venetz D, Heller M, Uguccioni M, Legler D F, Lacey C J, Coatesworth A, Polak W G, Cupedo T, Manoury B, Thelen M, Stein J V, Wolf M, Leake M C, Timmis J, Ludewig B, Coles M C. B cell zone reticular cell microenvironments shape CXCL13 gradient formation. Nat Commun 2020; 11:3677.
   
type journal paper/review (English)
date of publishing 22-07-2020
journal title Nat Commun (11/1)
ISSN electronic 2041-1723
pages 3677
PubMed 32699279
DOI 10.1038/s41467-020-17135-2