CCR8 Mediated Cell Migration Controls Th2 Differentiation

Rationale: In mouse models, allergen exposure leads to the selective migration of Th2-inducing CD301b⁺ dendritic cells (DCs) from the skin to the draining lymph node (dLN).  The chemokine receptor CCR7 is necessary for DC migration to the dLN, but whether other chemokine networks control the migration of specific DC subsets is unknown.  We hypothesized that allergen exposure induces novel chemokine pathways that specifically promote the migration of CD301b⁺ DCs.

Methods: We utilized the papain model of allergic inflammation in the mouse.  Quantitative PCR was performed to examine chemokine ligand expression.  Flow cytometry, confocal microscopy, and in vitro restimulation assays were utilized to study DC migration and subsequent immune activation in response to papain exposure.  

Results: Exposure to the protease allergen papain induced the production of CCL8, a known ligand of CCR8.  CD301b⁺ DCs from CCR8 deficient mice exhibited decreased migration from the skin to the dLN after papain immunization.  Furthermore, CCR8 deficient CD301b⁺ DCs that were found in the dLN exhibited altered localization within the dLN.  These defects in CD301b⁺ DC migration and localization were accompanied by defects in Th2 differentiation. 

Conclusions: We provide evidence that CCR8 mediated signaling promotes the specific migration and localization of Th2-inducing CD301b⁺ DCs, thereby controlling the induction of Th2 differentiation.  These data reveal the CCR8 pathway as a target for preventing allergic immune initiation.  Additionally, it may indicate a broader role for alternative chemokine networks in the selective migration of DC subsets.