Mammalian and viral IL-10 enhance C-C chemokine receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: Impact on chemotactic responses and in vivo homing ability

The immunosuppressive and anti-inflammatory cytokine IL-10 inhibits the phe notypic and functional maturation of dendritic cells (DC) and has been repo rted to confer tolerogenic properties on these important professional APC. Here, we exposed murine bone marrow-derived myeloid DC to either mouse (m) or viral (v) IL-10 early during their in vitro generation in response to GM -CSF and IL-4. Both mIL-10 and vIL-10 down-regulated the expression of CCR7 mRNA determined by RT-PCR, while mIL-10 up-regulated the expression of CCR 5 transcripts. These changes in CCR7 and CCR5 expression were associated wi th inhibition and augmentation, respectively, of DC chemotaxis toward their respective agonists, macrophage inflammatory proteins 3 beta and 1 alpha, while in vivo homing of DC from peripheral s.c. sites to secondary lymphoid tissue of syngeneic or allogeneic recipients was significantly impaired. A nti-mIL-10R mAb reversed the effects of mIL-10 on CCR expression and restor ed DC homing ability. Retroviral transduction of mIL-10- and vIL-10-treated DC to overexpress transgenic CCR7 partially restored the cells' lymphoid t issue homing ability in allogeneic recipients. However, CCR7 gene transfer did not reinstate the capacity of IL-10-treated DC to prime host naive T ce lls for ex vivo proliferative responses or Th1 cytokine (IFN-gamma) product ion in response to rechallenge with (donor) alloantigen. These findings sug gest that in addition to their capacity to subvert DC maturation/function a nd confer tolerogenic potential on these cells, mIL-10 and vIL-10 regulate DC migratory responses via modulation of CCR expression.