Comparison of stimulatory and inhibitory dendritic cell subsets reveals new role of DC in granulomatous infection

Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. Recently we demonstrated that infection of human DC with intracellular bacterium Listeria monocytogenes (L.monocytogenes) leads to the induction of the immunoinhibitory enzyme indoleamine 2,3-dioxygenase (Popov et al., J Clin Invest, 2006), while in the previous studies L.monocytogenes infection was associated with a rather stimulatory DC phenotype. To clarify this discrepancy we performed comparative microarray analysis of immature mo-DC (immDC), mature stimulatory mo-DC (matDC) and mature inhibitory DC either stimulated with prostaglandin E2 (PGE2-DC) or infected with L.monocytogenes (infDC). Studying infection of human myeloid DC with Listeria monocytogenes, we found out, that infected DC are modified by the pathogen to express multiple inhibitory molecules, including indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2, interleukin 10 and CD25, which acts on DC as IL-2 scavenger. All these inhibitory molecules, expressed on regulatory DC (DCreg), are strictly TNF-dependent and are in concert suppressing T-cell responses. Moreover, only DCreg can efficiently control the number of intracellular listeria, mostly by IDO-mediated mechanisms and by other factors, remaining to be identified. Analyzing publicly acessible data of transcriptional changes in DC and macrophages, infected by various pathogens and parasites (GEO, GSE360), we noticed that infection of these cells with Mycobacterium tuberculosis causes transcriptional response, comparable with the one caused by listeria in human DC. In fact, granuloma in tuberculosis and listeriosis in vivo are enriched for myeloid DC and macrophages characterized by regulatory phenotype.

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Popov A, Driesen J, Abdullah Z, Wickenhauser C, Beyer M, Debey-Pascher S, Saric T, Kummer S, Takikawa O, Domann E, Chakraborty T, Krönke M, Utermöhlen O, Schultze JL