Defective CCR7 function in aging: implications for dendritic cell migration (B156)

Abstract We recently reported that bone marrow-derived dendritic cells (DCs) from old C57BL/6 mice are less effective than their young counterpart in inducing the regression of pre-established B16-OVA melanomas. However, the mechanisms for this are unclear. DCs migration to lymphoid organs is essential to effective DC anti-tumor activity and is regulated by interactions between CCR7 and its ligands CCL21 and CCL19. We therefore examined the effect of aging on DC migration, CCR7 expression and function. Young (3–6 months) and old (18–20 months) DCs were labeled with CFSE and CMPTX, and their in vivo migration quantified by fluorescent microscopy. Half as many aged DCs were present in the popliteal lymph nodes (p<0.025). DCs from aged mice express 50% less CCR7 compared to young DCs (p< 0.0005). Surprisingly, the reduced gene expression did not result in any significant change in CCR7 surface expression on DCs. Nevertheless, the reduced CCR7 gene expression correlated with the impaired in vitro migration of aged DCs in response to CCL21 (p< 0.05). Finally, we showed that aged DCs have impaired signaling following exposure to CCL21. In conclusion, our data showed that old DCs have defective in vivo migration that correlates with reduced CCR7 gene expression, as well as impaired in vitro CCL21 migratory response and signaling. These findings may contribute to the observed impaired DC tumor immunotherapeutic response in aging.