ABSTRACT
Antibody-secreting plasma cells are nonrecirculatory and lodge in splenic red pulp, lymph node medullary cords, and bone marrow. The factors that regulate plasma cell localization are poorly defined. Here we demonstrate that, compared with their B cell precursors, plasma cells exhibit increased chemotactic sensitivity to the CXCR4 ligand CXCL12. At the same time, they downregulate CXCR5 and CCR7 and have reduced responsiveness to the B and T zone chemokines CXCL13, CCL19, and CCL21. We demonstrate that CXCL12 is expressed within splenic red pulp and lymph node medullary cords as well as in bone marrow. In chimeric mice reconstituted with CXCR4-deficient fetal liver cells, plasma cells are mislocalized in the spleen, found in elevated numbers in blood, and fail to accumulate normally in the bone marrow. Our findings indicate that as B cells differentiate into plasma cells they undergo a coordinated change in chemokine responsiveness that regulates their movements in secondary lymphoid organs and promotes lodgment within the bone marrow.
Subject(s)
Chemokines, CXC/metabolism , Chemokines/metabolism , Plasma/cytology , Plasma/metabolism , Receptors, CXCR4/metabolism , Animals , Bone Marrow/metabolism , Cell Movement , Chemokine CCL19 , Chemokine CCL21 , Chemokine CXCL12 , Chemokine CXCL13 , Chemokines, CC/metabolism , Chemokines, CXC/genetics , Female , Lymph Nodes/physiology , Male , Mice , Mice, Inbred Strains , Mice, Mutant Strains , Receptors, CCR7 , Receptors, CXCR4/genetics , Receptors, CXCR5 , Receptors, Chemokine/metabolism , Receptors, Cytokine/metabolism , Spleen/physiologyABSTRACT
The spontaneous mutant mouse strain, plt/plt, lacks the secondary lymphoid organ chemokine (SLC)-ser gene and has disrupted trafficking of T cells and dendritic cells (DCs) to lymphoid tissues. We demonstrate here that the gene for the related chemokine, Epstein-Barr virus-induced molecule-1 ligand chemokine (ELC), is also deleted in this immunodeficient mouse strain. Using a combination of approaches, including bone marrow reconstitution and double in situ hybridization, we show in wild-type mice that ELC is expressed by T zone stromal cells that also make SLC. Smaller amounts of ELC are made by DCs, predominantly of the CD8(+) phenotype. We propose that ELC- and SLC-expressing T zone stromal cells play a central role in bringing naive T cells and DCs together for the initiation of immune responses.
Subject(s)
Chemokines, CC/genetics , Animals , Base Sequence , Chemokine CCL19 , Chemokine CCL21 , Codon, Initiator , DNA, Complementary , Dendritic Cells/metabolism , Gene Expression , Lymphoid Tissue/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Molecular Sequence Data , Stromal Cells/metabolism , Tissue DistributionABSTRACT
Follicular dendritic cells (FDCs), the best defined stromal cell subset within lymphoid follicles, play a critical role in presenting intact antigen to B lymphocytes. The discovery that many follicular stromal cells make B-lymphocyte chemoattractant (BLC), a CXC chemokine that attracts CXCR5+ cells, provides a basis for understanding how motile B cells come into contact with stationary FDCs. Here we review our work on BLC and discuss properties of BLC-expressing follicular stromal cells. We also review the properties of primary follicle and germinal center FDCs and suggest a model of FDC development that incorporates information about BLC expression. Finally, we consider how antigen recognition causes T and B lymphocytes to undergo changes in chemokine responsiveness that may help direct their movements into, or out of, lymphoid follicles.
Subject(s)
Dendritic Cells, Follicular/cytology , Dendritic Cells, Follicular/immunology , Lymphocytes/cytology , Lymphocytes/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cell Movement , Chemokine CXCL13 , Chemokines, CXC/metabolism , Humans , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Lymphotoxin-alpha/metabolism , Mice , Models, Biological , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Lymphoid follicles are B-cell-rich compartments of lymphoid organs that function as sites of B-cell antigen encounter and differentiation. CXC chemokine receptor-5 (CXCR5) is required for B-cell migration to splenic follicles, but the requirements for homing to B-cell areas in lymph nodes remain to be defined. Here we show that lymph nodes contain two types of B-cell-rich compartment: follicles containing follicular dendritic cells, and areas lacking such cells. Using gene-targeted mice, we establish that B-lymphocyte chemoattractant (BLC/BCA1) and its receptor, CXCR5, are needed for B-cell homing to follicles in lymph nodes as well as in spleen. We also find that BLC is required for the development of most lymph nodes and Peyer's patches. In addition to mediating chemoattraction, BLC induces B cells to up-regulate membrane lymphotoxin alpha1beta2, a cytokine that promotes follicular dendritic cell development and BLC expression, establishing a positive feedback loop that is likely to be important in follicle development and homeostasis. In germinal centres the feedback loop is overridden, with B-cell lymphotoxin alpha1beta2 expression being induced by a mechanism independent of BLC.
