| Priming of T cell responses involves the capture of antigen by immature dendritic cells (DCs) followed by a maturation process involving antigen processing, migration to secondary lymphoid tissue, induction of proinflammatory cytokines and costimulatory molecules and transport of peptide-MHC complexes to the cell surface. Certain members of the toll-like receptor (TLR) family and the tumor necrosis factor (TNF) receptor family transduce signals for DC maturation. However, additional receptors may also regulate DC maturation, reflecting the complexity of signals that participate in the initiation of adaptive immunity. We show here that immature human myeloid and plasmacytoid DCs express the B7 family member, B7-DC. B7-DC predominantly serves a stimulatory rather than inhibitory function in the human system. Along with CD3, it costimulates naive and resting T cells to proliferate and produce proinflammatory cytokines. Moreover, it works in concert with B7-1 in its ability to activate the adaptive arm of the immune response. We also show that B7-DC expressed on the surface of an antigen presenting cell has a broader role than as a T cell costimulatory molecule. Cross-linking of B7-DC on immature myeloid DCs by plate-bound anti-B7-DC antibodies induces multiple features of DC maturation including activation of NF-kappaB and MAP kinase signaling, resulting in enhanced capacity to present antigen and activate T cells. DCs stimulated through B7-DC produce proinflammatory cytokines, induce T cell transmigration, and stimulate proliferation and activation of allogeneic and antigen specific T cell responses. Moreover, anti-B7-DC activated DCs down-regulate their phagocytic ability, as is the case during DC maturation, but interestingly have an initial enhancement of phagocytosis early in their maturation process. Cross-linking of B7-DC on plasmacytoid DCs induces type I interferon release at levels comparable to that induced by viral infection. These results suggest that, in addition to its role as a T cell costimulatory molecule, B7-DC serves a second role as a conduit for dendritic cell maturation. |
