Nitric oxide controls an inflammatory-like Ly6ChiPDCA1+ DC subset that regulates Th1 immune responses

NO produced by DCs suppresses a Ly6ChiPDCA1+ DC subpopulation resembling inflammatory DCs, highly responsive to TLR stimulation and capable of initiating strong Th1 immune responses. Using NOS2 KO mice, we investigated the hypothesis that NO modulation of BM‐DC contributes to the NO‐mediated control of Th1 immune responses. BM‐DCs from NOS2 KO mice, compared with WT BM‐DCs, have enhanced survival and responsiveness to TLR agonists, develop more Ly6ChiPDCA1+ DCs that resemble inflammatory DCs and produce high levels of inflammatory cytokines. Also, compared with WT‐infected mice, NOS2 KO mice infected with WNV showed enhanced expansion of a similar inflammatory Ly6ChiPDCA1+ DC subset. Furthermore, in contrast to WT DCs, OVA‐loaded NOS2 KO BM‐DCs promoted increased IFN‐γ production by OTII CD4+ T cells in vitro and when adoptively transferred in vivo. The addition of a NO donor to NOS2 KO BM‐DCs prior to OTII T cells priming in vivo was sufficient to revert Th1 immune responses to levels induced by WT BM‐DCs. Thus, autocrine NO effects on maturation of inflammatory DCs and on DC programming of T cells may contribute to the protective role of NO in autoimmune diseases and infections. Regulating NO levels may be a useful tool to shape beneficial immune responses for DC‐based immunotherapy.