The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response

The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b+ DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b+ DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b+ DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169+SIGN-R1+ macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b+ DC migration. In CCR8-deficient mice, CD301b+ DCs remained in the SCS and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined a CCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169+SIGN-R1+ macrophages control the polarization of the adaptive immune response. [Display omitted] •Allergen exposure promotes CD301b+ DC LN migration without upregulating CCR7•CD169+SIGN-R1+ macrophages produce CCL8 in the LN in response to allergen exposure•CCL8 and CCL21 synergize in a Src-dependent manner to augment CD301b+ DC migration•CD301b+ DCs require CCR8 expression to enter the LN and promote Th2 differentiation Migration of dendritic cells (DCs) into the lymph node (LN) initiates adaptive immunity and is thought to be solely dependent on CCR7. Sokol et al. show that in a cutaneous type 2 immune response, CCR8 synergizes with CCR7 and is necessary to promote the entry of allergen-activated DCs into the LN parenchyma, which is required for Th2 differentiation.