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Processing and Presentation of Variant Surface Glycoprotein Molecules to T Cells in African Trypanosomiasis¹

Taylor R. Dagenais^*, Bailey E. Freeman, Karen P. Demick^*,, Donna M. Paulnock and John M. Mansfield^2,*

^* Department of Bacteriology and Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706

Th1 cell responses to the variant surface glycoprotein (VSG) of African trypanosomes play a critical role in controlling infection through the production of IFN-, but the role of APCs in the induction and regulation of T cell-mediated protection is poorly understood. In this study, we have investigated the Ag presentation capabilities of dendritic cells (DCs) and macrophages during early trypanosome infection in relatively resistant responder and susceptible nonresponder mouse strains. Splenic DCs appeared to be the primary cell responsible for activating naive VSG-specific Th cell responses in resistant responder animals through the coordinated up-regulation of costimulatory molecules, secretion of IL-12, and presentation of VSG peptides to T cells in vivo. Splenic DC depletion and the down-regulation of costimulatory markers on splenic macrophages were observed in susceptible animals and may be associated with the inability of these animals to elicit a significant VSG-specific T cell response. In contrast to splenic APCs, peritoneal macrophages secreted NO, failed to activate naive Th cells in vitro, and presented relatively low levels of VSG peptides to T cells in vivo. Thus, VSG-specific Th1 cell responses may be determined by tissue- and cell-specific differences in Ag presentation. Additionally, all APCs from resistant and susceptible strains displayed a reduced ability to process and present newly encountered exogenous Ag, including new VSG molecules, during high parasitemia. Thus, initial uptake of VSG (or other trypanosome factors) may interfere with Ag presentation and have dramatic consequences for subsequent T cell responses to other proteins.

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 Grants AI-22441 and AI-073346 (to J.M.M.), and AI-048242 and AI-051421 (to D.M.P.) from the U.S. Public Health Service.

² Address correspondence and reprint requests to Dr. John M. Mansfield, Department of Bacteriology, Microbial Sciences Building, 1550 Linden Drive, University of Wisconsin-Madison, Madison, WI 53716. E-mail address: mansfield{at}bact.wisc.edu

³ Abbreviations used in this paper: VSG, variant surface glycoprotein; DC, dendritic cell; VAT, variant antigenic type; MHC II, MHC class II; HEL, hen egg lysozyme; MFI, mean fluorescence intensity.