Granulomas represent a localized inflammatory reaction that is characteristically observed in many inflammatory conditions. However, the mechanisms of granuloma formation have not been fully defined. Herein we demonstrate, by using experimental models of intestinal inflammation, that a unique CD11c⁺ DC-like cell subset that exhibits phenotypic and functional features of immature myeloid DCs and is characterized by the expression of a macrophage marker (F4/80) produces large amounts of IL-23 and directly induces the development of granulomas under a Th1-predominant intestinal inflammatory condition. Importantly, both IL-4 and IgG contribute to the suppression of F4/80⁺ DC-like cell–mediated granuloma formation by regulating the function and differentiation of this cell subset. In addition, enteric flora is required for the F4/80⁺ DC-like cell–mediated granuloma formation. Collectively, our data provide what we believe are novel insights into the involvement of F4/80⁺ DC-like cells in intestinal granuloma formation and demonstrate the role of host (IL-4 and IgG) and environmental (enteric flora) factors that regulate this function.