Certain classes of dendritic cells (DCs) meet rare cognate Ag-specific T and B cells inside primary B cell follicles for the development of germinal centers. However, the mechanisms underlying this coordination are still undefined. Cysteine-rich (CR) domain of the mannose receptor (CR-Fc)+ DCs are a newly discovered subset of DCs that migrate rapidly into the primary lymphoid follicles from marginal zone after immunization. In this work, we uncover the key role of B cells in the establishment of a microenvironment that allows these DCs to be in the B cell area in a lymphotoxin (LT)-dependent fashion. CR-Fc+ DCs are absent from the spleens of both LTβR- and LTα-deficient mice, suggesting that signaling by membrane LT is required for the presence of CR-Fc+ DCs in the spleen. Interestingly, analysis of mutant mice that lack T, B, or NK cells demonstrates that B cell-derived membrane LT is essential for the unique localization of CR-Fc+ DCs in the spleen. Using bone marrow transfer and ligand-blocking approaches, we provide evidence that B cell-derived LT acts indirectly on CR-Fc+ DCs through LTβR+ stromal cells. In analogous fashion to certain Ag-activated T and B cells, CR-Fc+ DCs, expressing CXCR5, localize to primary lymphoid follicles in response to CXC ligand 13 (B lymphocyte chemoattractant). Together, we propose that B cells play a central role in establishing the chemotactic gradient that attracts not only Ag-activated T and B cells but also Ag-carrying CR-Fc+ DCs. In turn, CR-Fc+ DCs and T cells home to B cell follicles to interact with B cells in the developing germinal center.
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