The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse.

Among dendritic cell (DC) subsets, CD8alpha(+) DCs and plasmacytoid DCs (pDCs) produce high levels of IL12 and type I interferons (IFNs), respectively, and confer early innate immunity. Development of CD8alpha(+) DCs and pDCs requires the interferon regulatory factor 8 (IRF8). Recently, a spontaneous point mutation was identified in the Irf8/Icsbp gene in the BXH2 mouse, which exhibits an immunodeficient phenotype similar to the IRF8 knockout (KO) mouse. We show that this mutation, designated IRF8(R294C), abolishes the development of CD8alpha(+) DCs without impairing pDC development, and eliminates production of IL12p40, while retaining that of type I IFNs. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that IRF8(R294C) failed to interact with partner transcription factors and did not bind certain promoters that require partner interactions. Together, this work indicates that IRF8-partner interactions play different roles in CD8alpha(+) DCs and pDCs, revealing a mechanistic separation that underlies development of these DC subsets.