Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells.
Although CD8(+) T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8(+) T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8(+) T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8(+) and CD4(+) T cell responses. Furthermore, we show that P. berghei-expressed antigens are cross-presented by the CD8alpha(+) subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM.
Lundie
Rachel J
RJ
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
de Koning-Ward
Tania F
TF
Davey
Gayle M
GM
Nie
Catherine Q
CQ
Hansen
Diana S
DS
Lau
Lei Shong
LS
Mintern
Justine D
JD
Belz
Gabrielle T
GT
Schofield
Louis
L
Carbone
Francis R
FR
Villadangos
Jose A
JA
Crabb
Brendan S
BS
Heath
William R
WR
D000818:Animals; D030801:Animals, Genetically Modified; D000953:Antigens, Protozoan / Q000276:immunology*; D001921:Brain / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D008018:Life Cycle Stages; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D010962:Plasmodium berghei / Q000235:genetics / Q000254:growth & development / Q000276:immunology*
D000953:Antigens, Protozoan; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte
Methods. 1997 Oct;13(2):134-47
9405197
Immunol Cell Biol. 1998 Feb;76(1):34-40
9553774
J Immunol. 1996 Aug 1;157(3):978-83
8757600
J Immunol. 2004 May 1;172(9):5553-60
15100298
J Immunol. 2003 Feb 15;170(4):2221-8
12574396
Science. 1990 Dec 21;250(4988):1720-3
2125367
J Immunol. 2003 May 1;170(9):4437-40
12707318
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10729-34
16807294
J Immunol. 1993 Nov 1;151(9):4811-20
8409439
Parasitology. 1997 Jan;114 ( Pt 1):7-12
9011069
J Immunol. 2007 May 15;178(10):6033-7
17475826
Immunity. 1994 Apr;1(1):73-83
7889402
Int J Parasitol. 2006 Apr;36(4):485-96
16500656
J Cell Biol. 2003 Sep 1;162(5):877-87
12952938
Cell. 1994 Jan 14;76(1):17-27
8287475
Immunity. 2002 Aug;17(2):211-20
12196292
J Immunol. 2005 Jul 1;175(1):196-200
15972648
Immunol Rev. 2004 Jun;199:9-26
15233723
Proc Natl Acad Sci U S A. 1989 Jul;86(14):5572-4
2501793
J Exp Med. 2002 May 20;195(10):1371-7
12021316
J Exp Med. 2006 Jun 12;203(6):1427-33
16754719
Curr Opin Immunol. 1999 Aug;11(4):412-9
10448141
Parasite Immunol. 2006 Jan-Feb;28(1-2):15-24
16438672
J Exp Med. 2000 Dec 18;192(12):1685-96
11120766
Mol Biochem Parasitol. 1997 Jun;86(2):155-62
9200122
J Immunol. 2002 Dec 1;169(11):6369-75
12444144
Int J Parasitol. 2006 May 1;36(5):547-54
16600241
J Immunol. 2007 May 1;178(9):5779-88
17442962
Science. 1987 Sep 4;237(4819):1210-2
3306918
Mol Biochem Parasitol. 2004 Sep;137(1):23-33
15279948
Immunol Cell Biol. 2002 Apr;80(2):156-63
11940116
Redox Rep. 1999;4(6):333-5
10772080
Mol Cell Biol. 1985 Dec;5(12):3610-6
3915782
Int Immunol. 1999 Sep;11(9):1553-62
10464176
J Immunol. 1996 Aug 15;157(4):1620-4
8759747
Nat Protoc. 2006;1(1):346-56
17406255