B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion.
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 LTbetaR- and LTalpha-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 LTbetaR(+) 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.
Yu
Ping
P
Department of Pathology and Committee on Immunology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Wang
Yang
Y
Chin
Robert K
RK
Martinez-Pomares
Luisa
L
Gordon
Siamon
S
Kosco-Vibois
Marie H
MH
Cyster
Jason
J
Fu
Yang-Xin
YX
D000818:Animals; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000502:physiology*; D003545:Cysteine / Q000032:analysis / Q000235:genetics; D020566:Dendritic Cells, Follicular / Q000737:chemistry / Q000166:cytology* / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000032:analysis / Q000235:genetics; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000032:analysis; D013154:Spleen / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology
C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D007141:Immunoglobulin Fc Fragments; C505697:LTBR protein, human; D008024:Ligands; D008070:Lipopolysaccharides; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D003545:Cysteine