Dendritic cell biology and regulation of dendritic cell trafficking by chemokines

DC (dendritic cells) represent an heterogeneous family of cells which funct ion as sentinels of the immune system. They traffic from the blood to the t issues where, while immature, they capture antigens. Then, following inflam matory stimuli, they leave the tissues and move to the draining lymphoid or gans where, converted into mature DC, they prime naive T cells. The key rol e of DC migration ill their sentinel function led to the investigation of t he chemokine responsiveness of DC populations during their development and maturation. These studies have shown that immature DC respond to many CC an d CXC chemokines (MIP-1 alpha, MIP-1 beta, MIP-3 alpha, MIP-5, MCP-3, MCP-4 , RANTES, TECK and SDF-1) which are inducible upon inflammatory stimuli. Im portantly, each immature DC population displays a unique spectrum of chemok ine responsiveness, For examples, Langerhans cells migrate selectively to M IP-3 alpha (via CCR6), blood CD11c(+) DC to MCP chemokines (via CCR2), mono cytes derived-DC respond to MIP-1 alpha/beta (via CCR1 and CCR5), while blo od CD11c(-) DC precursors do not respond to any of these chemokines. All th ese chemokines are inducible upon inflammatory stimuli, in particular MIP-3 alpha, which is only detected within inflamed epithelium, a site of antige n entry known to be infiltrated by immature DC. In contrast to immature DC, mature DC lose their responsiveness to most of these inflammatory chemokin es through receptor down-regulation or desensitization, but acquire respons iveness to ELC/MIP-3 beta and SLC/6Ckine as a consequence of CCR7 up-regula tion. ELC/MIP-3 beta and SLC/6Ckine are specifically expressed in the T-cel l-rich areas where mature DC horne to become interdigitating DC. Altogether , these observations suggest that the inflammatory chemokines secreted at t he site of pathogen invasion will determine the DC subset recruited and wil l influence the class of the immune response initiated. In contrast, MIP-3 beta /6Ckine have a determinant role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node, as illustrated b y recent observations in mice deficit nt for CCR7 or SLC/6Ckine. A better u nderstanding of the regulation of DC trafficking might offer new opportunit ies of therapeutic interventions to suppress, stimulate or deviate the immu ne response.