Recombination Activating Gene-2 Regulates CpG-Mediated Interferon-α Production in Mouse Bone Marrow-Derived Plasmacytoid Dendritic Cells

Using mice that lack recombination activating gene-2 (Rag2), we have found that bone marrow-derived plasmacytoid dendritic cells (pDCs) as main producers of interferon-alpha (IFN alpha) require Rag2 for normal development. This is a novel function for Rag2, whose classical role is to initiate B and T cell development. Here we showed that a population of common progenitor cells in the mouse bone marrow possessed the potential to become either B cells or pDCs upon appropriate stimulations, and the lack of Rag2 hindered the development of both types of progeny cells. A closer look at pDCs revealed that Rag2(-/-) pDCs expressed a high level of Ly6C and were defective at producing IFN alpha in response to CpG, a ligand for toll-like receptor 9. This phenotype was not shared by Rag1(-/-) pDCs. The induction of CCR7, CD40 and CD86 with CpG, however, was normal in Rag2(-/-) pDCs. In addition, Rag2(-/-) pDCs retained the function to promote antibody class switching and plasma cell formation through producing IL-6. Further analysis showed that interferon regulatory factor-8, a transcription factor important for both IFNa induction and pDC development, was dysregulated in pDCs lacking Rag2. These results indicate that the generation of interferon response in pDCs requires Rag2 and suggest the lymphoid origin of bone marrow-derived pDCs.