Direct Sensing of Toll-Like Receptor Agonists by Dendritic Cell Progenitors Leads to Their Homing to Inflamed Lymph Nodes Via Regulation of CXCR4 and CCR7

Abstract 3895

Dendritic cells (DCs), the key antigen-presenting cell population, continuously need to be regenerated from bone marrow (BM) hematopoietic stem and progenitor cells. Common dendritic progenitors (CDP) were previously shown to efficiently generate DCs in lymphoid and non-lymphoid tissues. How the dissemination of bone marrow (BM) DC-progenitors to peripheral tissues is regulated upon demand remains elusive to date. Acute microbial infections are sensed via Toll-like receptors (TLR). Recent studies showed that stem and progenitor cells express TLRs. We found that CDPs in the BM of mice express relative high levels of Tlr2, Tlr4 and Tlr9, and hypothesized that these might be involved in regulating CDP migration. CDPs in steady-state expressed high levels of Cxcr4, but no, or low Ccr7. Upon direct stimulation with the respective TLR-agonists in vitro, CDPs rapidly down-regulated Cxcr4 and up-regulated Ccr7 mRNA and protein. CDPs that were stimulated with TLR-agonists for only 2 h preferentially homed to the lymph nodes (LN) in expense of BM in steady-state recipients. When TLR-agonists were injected subcutaneously, CDPs gave rise to increased numbers of plasmacytoid DCs, classical DCs, and DCs with a skin-derived migratory phenotype in inflamed LNs on day 4. This was not due to increased proliferative activity. Injecting the CXCR4 antagonist AMD3100 demonstrated that the retention of CDPs in the BM depends on CXCR4. Furthermore, CCR7 was important for the engraftment of CDP-derived DCs into LNs in steady-state and during inflammation. In conclusion, DC progenitors in the bone marrow are capable to directly sense TLR-agonists via their cognate receptors in systemic infections. This results in differential expression of chemokine receptors and consecutive migration of DC-progenitors to inflamed LNs. This mechanism helps to restore DC subsets during ongoing immune responses and to return to DC homeostasis once the inflammation ceases.