Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis.
Despite their widespread expression, the in vivo recruitment activities of CCL19 (EBV-induced molecule 1 ligand chemokine) and CXCL12 (stromal cell-derived factor 1) have not been established. Furthermore, although CXCL13 (B lymphocyte chemoattractant) has been shown to induce lymphoid neogenesis through induction of lymphotoxin (LT)alpha1beta2, it is unclear whether other homeostatic chemokines have this property. In this work we show that ectopic expression in pancreatic islets of CCL19 leads to small infiltrates composed of lymphocytes and dendritic cells and containing high endothelial venules and stromal cells. Ectopic CXCL12 induced small infiltrates containing few T cells but enriched in dendritic cells, B cells, and plasma cells. Comparison of CCL19 transgenic mice with mice expressing CCL21 (secondary lymphoid tissue chemokine) revealed that CCL21 induced larger and more organized infiltrates. A more significant role for CCL21 is also suggested in lymphoid tissues, as CCL21 protein was found to be present in lymph nodes and spleen at much higher concentrations than CCL19. CCL19 and CCL21 but not CXCL12 induced LTalpha1beta2 expression on naive CD4 T cells, and treatment of CCL21 transgenic mice with LTbetaR-Fc antagonized development of organized lymphoid structures. LTalpha1beta2 was also induced on naive T cells by the cytokines IL-4 and IL-7. These studies establish that CCL19 and CXCL12 are sufficient to mediate cell recruitment in vivo and they indicate that LTalpha1beta2 may function downstream of CCL21, CCL19, and IL-2 family cytokines in normal and pathological lymphoid tissue development.
Luther
Sanjiv A
SA
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414, USA.
Bidgol
Afshin
A
Hargreaves
Diana C
DC
Schmidt
Andrea
A
Xu
Ying
Y
Paniyadi
Jyothi
J
Matloubian
Mehrdad
M
Cyster
Jason G
JG
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology* / Q000276:immunology; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000096:biosynthesis; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D016601:RNA-Binding Proteins; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D012269:Ribosomal Proteins; D017154:Stromal Cells / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; C505887:Ltb protein, mouse; C505888:Ltb protein, rat; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D012269:Ribosomal Proteins; C069798:Rps15 protein, mouse; C484070:Rps15 protein, rat