title: Processing and presentation of variant surface glycoprotein molecules to T cells in African trypanosomiasis.
abstract: Th1 cell responses to the variant surface glycoprotein (VSG) of African trypanosomes play a critical role in controlling infection through the production of IFN-gamma, 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.
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Taylor R
authors.initials: TR
authors.lastname: Dagenais
authors.forename: Bailey E
authors.initials: BE
authors.lastname: Freeman
authors.forename: Karen P
authors.initials: KP
authors.lastname: Demick
authors.forename: Donna M
authors.initials: DM
authors.lastname: Paulnock
authors.forename: John M
authors.initials: JM
authors.lastname: Mansfield
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D016833:Trypanosoma brucei rhodesiense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
chemical_list: D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D014643:Variant Surface Glycoproteins, Trypanosoma
references.citation: J Leukoc Biol. 1998 Apr;63(4):429-39
references.pmid: 9544572
references.citation: Cell. 2002 Apr 5;109(1):5-8
references.pmid: 11955440
references.citation: J Immunol. 1990 May 15;144(10):4022-9
references.pmid: 1970594
references.citation: Exp Parasitol. 1970 Dec;28(3):521-34
references.pmid: 4993889
references.citation: Eur J Immunol. 1992 Oct;22(10):2741-4
references.pmid: 1396977
references.citation: J Exp Med. 2006 Jun 12;203(6):1427-33
references.pmid: 16754719
references.citation: Immunol Cell Biol. 1996 Dec;74(6):555-63
references.pmid: 8989594
references.citation: J Immunol. 1993 Apr 1;150(7):2910-9
references.pmid: 8454863
references.citation: Eur J Immunol. 1989 May;19(5):829-35
references.pmid: 2525474
references.citation: Parasitology. 1975 Dec;71(3):393-417
references.pmid: 645
references.citation: J Immunol. 1988 Jan 1;140(1):283-8
references.pmid: 3121739
references.citation: Infect Immun. 2000 Feb;68(2):848-60
references.pmid: 10639455
references.citation: J Immunol. 2003 Aug 15;171(4):1950-60
references.pmid: 12902498
references.citation: Parasite Immunol. 2000 Jul;22(7):361-70
references.pmid: 10886720
references.citation: Trends Genet. 1992 Dec;8(12):452-7
references.pmid: 1492370
references.citation: Ann Soc Belg Med Trop. 1992;72 Suppl 1:27-38
references.pmid: 1417167
references.citation: Infect Immun. 1999 Jun;67(6):3128-32
references.pmid: 10338530
references.citation: Infect Immun. 2003 Jun;71(6):3337-42
references.pmid: 12761116
references.citation: Int Immunol. 2003 Aug;15(8):993-1006
references.pmid: 12882837
references.citation: Exp Parasitol. 1992 Nov;75(3):353-60
references.pmid: 1426137
references.citation: Nature. 1993 Apr 15;362(6421):603-9
references.pmid: 8464512
references.citation: Mol Biochem Parasitol. 1992 Mar;51(1):119-32
references.pmid: 1373472
references.citation: Cytokine. 2000 Jul;12(7):1024-34
references.pmid: 10880248
references.citation: J Immunol. 1984 Sep;133(3):1564-9
references.pmid: 6747297
references.citation: Infect Immun. 1995 Apr;63(4):1563-6
references.pmid: 7890423
references.citation: Infect Immun. 2006 Aug;74(8):4530-7
references.pmid: 16861639
references.citation: Infect Immun. 1998 Feb;66(2):451-61
references.pmid: 9453595
references.citation: Am J Trop Med Hyg. 1982 Nov;31(6):1098-102
references.pmid: 6183984
references.citation: Toxicol In Vitro. 2001 Aug-Oct;15(4-5):319-25
references.pmid: 11566556
references.citation: J Immunol. 2007 Jul 1;179(1):548-56
references.pmid: 17579076
references.citation: Nature. 1987 Jan 1-7;325(6099):84-6
references.pmid: 2432433
references.citation: J Leukoc Biol. 2001 May;69(5):685-90
references.pmid: 11358974
references.citation: J Immunol. 1979 Mar;122(3):818-24
references.pmid: 376707
references.citation: Parasite Immunol. 1999 Feb;21(2):57-71
references.pmid: 10101716
references.citation: Parasitol Today. 1994 Jul;10(7):267-70
references.pmid: 15275443
references.citation: Parasite Immunol. 2005 Oct-Nov;27(10-11):361-71
references.pmid: 16179030
references.citation: Cell Immunol. 1980 Sep 1;54(2):414-24
references.pmid: 6448095
references.citation: J Immunol. 1983 Jan;130(1):405-11
references.pmid: 6847889
references.citation: J Immunol. 2005 Aug 15;175(4):2501-9
references.pmid: 16081822
references.citation: J Immunol. 1997 Jan 1;158(1):308-14
references.pmid: 8977204
references.citation: Res Immunol. 1993 Jun;144(5):370-6
references.pmid: 8278660
references.citation: J Immunol. 2003 Aug 1;171(3):1466-72
references.pmid: 12874239
references.citation: J Immunol. 1990 May 15;144(10):4011-21
references.pmid: 1692071
references.citation: Science. 1994 Feb 11;263(5148):814-7
references.pmid: 8303299
references.citation: J Immunol. 1993 Nov 15;151(10):5492-503
references.pmid: 8228241
references.citation: J Mol Evol. 1996 May;42(5):500-11
references.pmid: 8662002
references.citation: J Immunol. 1998 Dec 15;161(12):6775-83
references.pmid: 9862708
references.citation: J Cell Biol. 1997 May 5;137(3):715-27
references.pmid: 9151676
references.citation: J Infect Dis. 2001 Mar 15;183(6):988-91
references.pmid: 11237819
references.citation: J Parasitol. 1995 Dec;81(6):876-81
references.pmid: 8544057
references.citation: Cell Immunol. 1984 Aug;87(1):85-91
references.pmid: 6378394
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4022-7
references.pmid: 9108098
references.citation: Infect Immun. 1981 Jul;33(1):149-55
references.pmid: 6114926
references.citation: Biochem Biophys Res Commun. 1994 Dec 15;205(2):984-91
references.pmid: 7528505
references.citation: J Immunol. 2000 Mar 1;164(5):2379-85
references.pmid: 10679073
references.citation: Parasite Immunol. 1990 May;12(3):233-46
references.pmid: 2143570
references.citation: Infect Immun. 2009 Jan;77(1):141-51
references.pmid: 18936180
references.citation: J Immunol. 2002 Oct 1;169(7):3652-60
references.pmid: 12244157