Nitric oxide regulates TLR sensitivity and cytokine production by PDCA1+/Ly6C+ “inflammatory” dendritic cells and dendritic cell programming of Th1 immune responses. (90.28)

Abstract Studies using Nitric Oxide Synthase 2 knockout (NOS2 KO) mice have implicated nitric oxide (NO) in the control of Th1 T cells, autoreactive T cell and prevention of autoimmunity. We investigated whether the effect of NO on DCs might contribute to the NO-mediated control of Th1 immune responses. We found that GM-CSF and IL4-derived bone marrow DCs (GM/IL4-DCs) from NOS2 KO mice have enhanced survival and responsiveness to TLR signals compared to WT DCs. TLR stimuli induce a substantial up-regulation in NOS2 KO GM/IL4-DCs of a Ly6Ch DC subset characterized by: 1) high expression of co-stimulatory molecules and other maturation markers (CD86h/MHCIIh/PDCA1+); 2) a substantial increase in inflammatory cytokine production; and 3) decreased Mac3 expression compared to WT DCs. The DC subset dysregulated in the absence of NO resembles the recently described "inflammatory" DC. Furthermore, TLR-stimulated OVA-loaded, NOS2 KO GM/IL4-DCs compared to WT DCs induced increased IFNγ production of OTII CD4+ T cells either in vitro or in vivo. Our findings suggest that autocrine NO drives DC differentiation toward an "inflammatory" DC with a more macrophage phenotype and with lower co-stimulator/antigen-presenting capability and cytokine production, and thus toward a DC with less potential to activate Th1 immune responses. The [EC1]NO effects on DC programming of T cells may be crucial for the protective role of NO in autoimmune diseases. (Supported by NIH grants AI44257 and AI52203). [EC1]less potential for adaptive immunity, why would this be a good thing?