Abstract Autoimmunity ensues upon breakdown of tolerance mechanism and priming of self-reactive T cells. Plasmacytoid dendritic cells (pDCs) constitute a unique cell subset that participates in the activation of autoreactive T cells but also has been shown to be critically involved in the induction of self-tolerance. However, their functional importance during the priming phase of an organ-specific autoimmune response remains unclear. In this study, we demonstrate that absence of pDCs during myelin antigenic challenge resulted in amelioration of experimental autoimmune encephalomyelitis and reduced disease severity. This was accompanied by significantly decreased frequency of myelin-specific T cells in the draining lymph nodes and inhibition of Th1 and Th17 immune responses. Unexpectedly, in vivo ablation of pDCs increased myelopoiesis in the bone marrow and specifically induced the generation of CD11bhiGr1+ myeloid-derived suppressor cells (MDSCs). Furthermore, we demonstrate that pDC depletion enhanced the mobilization of MDSCs in the spleen, and that sorted MDSCs could potently suppress CD4+ T cell responses in vitro. Importantly, pDC-depleted mice showed increased levels of MCP-1 in the draining lymph nodes, and in vivo administration of MCP-1 increased the frequency and absolute numbers of MDSCs in the periphery of treated mice. Together, our results reveal that absence of pDCs during the priming of an autoimmune response leads to increased mobilization of MDSCs in the periphery in an MCP-1–dependent manner and subsequent amelioration of autoimmunity.