IRF4 Expression Is Required for the Immunoregulatory Activity of Conventional Type 2 Dendritic Cells in Settings of Chronic Bacterial Infection and Cancer.

The lamina propria of the gastrointestinal tract and other mucosal surfaces of humans and mice host a network of mononuclear phagocytes that differ in their ontogeny, surface marker and transcription factor expression, and functional specialization. Conventional dendritic cells (DCs) in particular exist as two major subpopulations in both lymphoid and nonlymphoid organs that can be distinguished based on their surface marker and transcription factor expression. In this study, we show in various Th1- and/or Th17-polarized settings of acute and chronic bacterial infection and of tumor growth that the conditional ablation of Irf4 in CD11c(+) DCs results in more efficient immune control of Helicobacter pylori, Mycobacterium bovis bacillus Calmette-Guerin, and Citrobacter rodentium and of tumor growth in a syngeneic tumor model. We attribute the phenotype of IRF4(Delta DC) mice to unrestricted Th1 responses and in particular to IFN-gamma- and TNF-alpha-expressing CD4(+) T cells. This activity of IRF4-expressing DCs is linked to a DC-specific immunoregulatory transcriptional program. In contrast, in Th2-polarized settings such as house dust mite-induced allergic airway inflammation, the lack of IRF4 expression in the DC compartment alleviates inflammation and goblet cell metaplasia. The combined data provide evidence for immunoregulatory properties of this versatile DC population in Th1-polarized infection settings.