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* Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637;
Sir William Dunn School of Pathology, Oxford, United Kingdom;
Serono Pharmaceutical Research Institute, Geneva, Switzerland; and
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143
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 LT
R- and
LT
-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 LTR+ 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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