VCAM-1 and VLA-4 Modulate Dendritic Cell IL-12p40 Production in Experimental Visceral Leishmaniasis

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Abstract
Vascular cell adhesion molecule-1 (VCAM-1) interacts with its major ligand very late antigen-4 (VLA-4) to mediate cell adhesion and transendothelial migration of leukocytes. We report an important role for VCAM-1/VLA-4 interactions in the generation of immune responses during experimental visceral leishmaniasis caused by Leishmania donovani. Our studies demonstrate that these molecules play no direct role in the recruitment of leukocytes to the infected liver, but instead contribute to IL-12p40-production by splenic CD8+ dendritic cells (DC). Blockade of VCAM-1/VLA-4 interactions using whole antibody or anti-VCAM-1 Fab′ fragments reduced IL-12p40 mRNA accumulation by splenic DC 5 hours after L. donovani infection. This was associated with reduced anti-parasitic CD4+ T cell activation in the spleen and lowered hepatic IFNγ, TNF and nitric oxide production by 14 days post infection. Importantly, these effects were associated with enhanced parasite growth in the liver in studies with either anti-VCAM-1 or anti-VLA-4 antibodies. These data indicate a role for VCAM-1 and VLA-4 in DC activation during infectious disease. VCAM-1 and its major ligand VLA-4 are adhesion molecules required for the recruitment and movement of leukocytes within tissue. In this study, we have investigated the role of these molecules during an experimental infection with Leishmania donovani, a protozoan parasite that causes a chronic disease called visceral leishmaniasis. Surprisingly, we showed that VCAM-1 and VLA-4 were not required for leukocyte migration into the liver, a site of acute L. donovani infection. Instead, there was a requirement for these molecules to initiate cell-mediated immune responses in the spleen within the first 5 hours of infection. When VCAM-1 was blocked during infection, early dendritic cell production of IL-12p40, a potent pro-inflammatory cytokine required for control of L. donovani, was suppressed, associated with a reduced parasite-specific T cell response in the spleen, and impaired immunity and parasite clearance in the liver. These results are important because they identify a novel role for VCAM-1 and VLA-4 in the regulation of dendritic cell activation during infectious disease.

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