Endocarditis is frequently attributable to oral streptococci, but mechanisms of pathogenesis are not well understood, although monocytes appear to be important. High titers of interleukin-12 (IL-12) are produced by peripheral blood mononuclear cells (PBMC) after engaging Streptococcus mutans, but monocytes in developing endocardial vegetations tend to disappear rather than become macrophages. These data prompted the hypothesis that streptococcus-infected monocytes differentiate into short-lived IL-12-producing dendritic cells (DCs) rather than macrophages. PBMC from healthy subjects were stimulated with six isolates of oral streptococci, three nonstreptococcal oral bacteria, or IL-4 plus granulocyte-macrophage colony-stimulating factor, and the appearance of cells with markers typical of mature DCs (CD83 ؉ , CD86 ؉ , CD11c ؉ , and CD14 ؊ ) was monitored. Supernatant fluids from the PBMC cultures were harvested and IL-12 p70 levels were determined. S. mutans-stimulated monocytes were analyzed for their ability to elicit allogeneic mixed-lymphocyte reactions. All streptococci examined, except one strain of Streptococcus oralis (35037), rapidly induced up-regulation of CD83 and CD86 and a loss of CD14 in the CD11c؉ monocyte population within 20 h. Induction of IL-12 was CD14 dependent and correlated with streptococcal isolates that promoted the DC phenotype. Major histocompatibility complex (MHC) class II expression was up-regulated by S. mutans, and these cells were short-lived and elicited potent allogeneic mixed-lymphocyte reactions typical of DCs. In summary, monocytes stimulated with endocarditis-associated oral streptococci rapidly exhibited the DC phenotype and functions. These data suggest that the initiation of bacterial endocarditis by oral streptococci may involve monocyte-to-DC differentiation, and this may help explain the low levels of macrophages in the site.Viridans group streptococci are the most common cause of native valve endocarditis, accounting for 45 to 80% of cases, and Streptococcus sanguis, Streptococcus mutans, Streptococcus gordonii, and Streptococcus oralis are frequently isolated from these lesions (35). Virulence factors such as exopolysaccharide (26), fibronectin binding protein (24), and platelet aggregation association protein (9, 17) have been implicated in the initial fibrin colonization on damaged cardiac valves. However, oral streptococci without these properties are also isolated from the endocarditis lesions.Monocytes are prominent in early endocarditis lesions, and the number of monocytes correlates with infectivity and higher tissue factor activity in vegetations (3, 6). However, the actual role of the monocytes in the initiation and perpetuation of the vegetation remains controversial. The work of Durack and Beeson indicates that the majority of S. sanguis strains in the vegetations are phagocytosed, transported in the blood, and deposited on the vegetations in adherent monocytes (13). The monocyte population then disappears, and viable bacteria persist in the vegetations....