Follicular Dendritic Cell Regulation of CXCR4-Mediated Germinal Center CD4 T Cell Migration

• Published in: The Journal of immunology (1950) Vol. 173; no. 10; pp. 6169 - 6178
• Main Authors: Estes, Jacob D, Thacker, Tyler C, Hampton, Denise L, Kell, Sariah A, Keele, Brandon F, Palenske, Emily A, Druey, Kirk M, Burton, Gregory F
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.11.2004
• Subjects: CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Migration Inhibition; Cells, Cultured; Chemokine CXCL12; Chemokine CXCL13; Chemokines, CXC - biosynthesis; Chemokines, CXC - physiology; Coculture Techniques; Dendritic Cells, Follicular - immunology; Dendritic Cells, Follicular - metabolism; Eye Proteins - biosynthesis; Eye Proteins - genetics; Gene Expression Regulation - immunology; GTPase-Activating Proteins - biosynthesis; GTPase-Activating Proteins - genetics; Humans; Palatine Tonsil; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - biosynthesis; Receptors, CXCR4 - physiology; RGS Proteins - biosynthesis; RGS Proteins - genetics; Signal Transduction - immunology; Sorting Nexins; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.10.6169

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.