MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells.
Upon stimulation by infectious agent products, dendritic cells (DC) become activated, express high levels of class I and class II antigens, CD80, CD86 and CD83 and migrate to secondary lymphoid organs where they can prime naive CD4-helper and CD8-cytotoxic T-cells. Cognate CD4(+) T-cell help mediated by CD40L along with DC stimulation with another T-cell effector molecule, termed lymphocyte activated gene-3 (LAG-3 or CD223, a ligand for MHC class II) have been shown to induce this maturation process. Both CD40L and LAG-3 have been used as vaccine adjuvants to induce CTL and CD4 Th1 responses. Here, we studied the effect of a soluble LAG-3Ig molecule on the chemokine and chemokine receptor profile of human immature monocyte-derived DC. LAG-3Ig, unlike CD40L, induced an inflammatory signal in terms of IL-8 and MIP-1alpha/CCL3 production and, in contrast to LPS, induced production of chemokines (MDC/CCL22 and TARC/CCL17) known to direct the migration of maturing DC to lymph nodes. In LAG-3-matured DC, surface expression of CCR5 (a receptor for MIP-1alpha/CCL3) was down-regulated and CCR7 (a receptor for MIP-3beta and SLC) was up-regulated. However, LAG-3-matured, but not LPS- or CD40L-matured DC retained their capacity to migrate in chemotaxis chambers and to respond to MIP-1alpha. Altogether, these data represent the first evidence that MHC class II signaling may affect DC migration to secondary lymphoid tissues.
Buisson
Sandrine
S
Laboratoire d'Immunologie des Tumeurs, Faculté de Pharmacie, 5, rue Jean-Baptiste Clément, 92296 Châtenay, Malabry, France.
Triebel
Frédéric
F
D015703:Antigens, CD; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics*; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C515370:CCR7 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human