Felix Czernilofsky, A. Mathioudaki, Lea Jopp-Saile, Raphael Lutz, Dominik Vonficht, Xi Wang, Christina Schniederjohann, Harald Voehringer, Tobias Roider, Marc-Andrea Baertsch, Claus Rodemer, Henry Löffler-Wirth, Michael Grau, Donnacha Fitzgerald, Johannes Mammen, Jan Kosla, Nora Liebers, P. Bruch, Diana Angelica Ordonez-Rueda, Alexander Brobeil, G. Mechtersheimer, Caroline Pabst, C. Müller-Tidow, Andreas Trumpp, Marc Seifert, Frank Neumann, Mathias Heikenwälder, Vladimir Benes, Wolfgang Huber, J. H. W. Distler, G. Lenz, H Binder, R Siebert, Garry P. Nolan, Moritz Gerstung, Judith B. Zaugg, Daniel Hübschmann, Simon Haas, Sascha Dietrich
Lymph node (LN) function requires the organization of cells into higher-order spatial units. However, the principles governing LN architecture in health and disease remain poorly understood. Here, we used single-cell and spatial mapping to investigate the mechanisms directing immune cell organization in human LNs and its disruption in architecturally distinct lymphoma entities: indolent follicular lymphoma (FL) and aggressive diffuse large B cell lymphoma (DLBCL). Our data substantiate the central role of LN-resident stromal cells in chemokine-driven lymphocyte zonation and reveal an inflammatory feedback loop fueled by tumor-reactive T cells that triggers stromal remodeling, progressive loss of homeostatic chemokine gradients, and tissue disorganization from a non-malignant state to FL and DLBCL. Loss of homeostatic chemokines was associated with adverse patient survival, identifying the underlying architectural rearrangement as a key event during lymphomagenesis. Collectively, our results highlight the principles of LN organization and suggest how lymphoma-induced microenvironmental reprogramming drives the loss of tissue organization.