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Functional Dichotomy of Dendritic Cells following Interaction with Leishmania braziliensis: Infected Cells Produce High Levels of TNF-, whereas Bystander Dendritic Cells Are Activated to Promote T Cell Responses¹

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19103

Leishmania braziliensis infections are often associated with exaggerated immune responses that can sometimes lead to severe disease associated with high levels of IFN- and TNF-. To explore the role played by dendritic cells (DCs) in these responses, we characterized DCs that were exposed to L. braziliensis. We found that DCs cultured with L. braziliensis parasites up-regulated DC activation markers and produced IL-12 and TNF-. However, not all DCs in the culture became infected, and an analysis of infected and uninfected DCs demonstrated that the up-regulation of activation markers and IL-12 production was primarily confined to the uninfected (bystander) DCs. Further studies with Transwell chambers and parasite fractions indicated that the activation of bystander DCs was mediated by a soluble parasite product, in a type 1 IFN- and MyD88-independent, but TNF--dependent fashion, and that the activated DCs were more efficient at presenting Ag than control DCs. In contrast, L. braziliensis-infected DCs failed to up-regulate activation markers, but exhibited a dramatic enhancement in their ability to produce TNF- in response to LPS as compared with uninfected DCs. These findings uncover a dual role for DCs in L. braziliensis infection: T cell activation by bystander DCs due to enhanced Ag-presenting capacity following exposure to soluble parasite products, and increased production of TNF- by infected cells that may contribute to the local control of the parasites, but concomitantly induce immunopathology.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Tropical Infectious Diseases Training Grant D43 TW007127 and Grants AI35914 and AI053825.

² Address correspondence and reprint requests to Dr. Phillip Scott, 380 South University Avenue, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19103. E-mail address: pscott{at}vet.upenn.edu

³ Abbreviations used in this paper: ML, mucosal; DC, dendritic cell; LPG, lipophosphoglycan; SLA, soluble Leishmania Ag.