Follicular dendritic cell regulation of CXCR4-mediated germinal center CD4 T cell migration.
Follicular dendritic cells (FDCs) up-regulate the chemokine receptor CXCR4 on CD4 T cells, and a major subpopulation of germinal center (GC) T cells (CD4(+)CD57(+)), which are adjacent to FDCs in vivo, expresses high levels of CXCR4. We therefore reasoned that GC T cells would actively migrate to stromal cell-derived factor-1 (CXCL12), the CXCR4 ligand, and tested this using Transwell migration assays with GC T cells and other CD4 T cells (CD57(-)) that expressed much lower levels of CXCR4. Unexpectedly, GC T cells were virtually nonresponsive to CXCL12, whereas CD57(-)CD4 T cells migrated efficiently despite reduced CXCR4 expression. In contrast, GC T cells efficiently migrated to B cell chemoattractant-1/CXCL13 and FDC supernatant, which contained CXCL13 produced by FDCs. Importantly, GC T cell nonresponsiveness to CXCL12 correlated with high ex vivo expression of regulator of G protein signaling (RGS), RGS13 and RGS16, mRNA and expression of protein in vivo. Furthermore, FDCs up-regulated both RGS13 and RGS16 mRNA expression in non-GC T cells, resulting in their impaired migration to CXCL12. Finally, GC T cells down-regulated RGS13 and RGS16 expression in the absence of FDCs and regained migratory competence to CXCL12. Although GC T cells express high levels of CXCR4, signaling through this receptor appears to be specifically inhibited by FDC-mediated expression of RGS13 and RGS16. Thus, FDCs appear to directly affect GC T cell migration within lymphoid follicles.
Estes
Jacob D
JD
Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA.
Thacker
Tyler C
TC
Hampton
Denise L
DL
Kell
Sariah A
SA
Keele
Brandon F
BF
Palenske
Emily A
EA
Druey
Kirk M
KM
Burton
Gregory F
GF
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology; D018920:Coculture Techniques; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D014066:Palatine Tonsil; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D058305:Sorting Nexins; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
C515255:CXCL12 protein, human; C110663:CXCL13 protein, human; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; D005136:Eye Proteins; D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C456322:RGS13 protein, human; C107413:RGS16 protein; D019718:Receptors, CXCR4; C442319:SNX13 protein, human; D058305:Sorting Nexins