Liver-Resident Memory CD8+T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection.
In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Daniel
D
Fernandez-Ruiz
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia.
Wei Yi
WY
Ng
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Lauren E
LE
Holz
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Joel Z
JZ
Ma
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Ali
A
Zaid
Liver Immunology Program, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Locked Bag No 6, Sydney, NSW 2042, Australia.
Yik Chun
YC
Wong
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Lei Shong
LS
Lau
The School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia.
Vanessa
V
Mollard
The School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia.
Anton
A
Cozijnsen
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Nicholas
N
Collins
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia.
Jessica
J
Li
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Gayle M
GM
Davey
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Yu
Y
Kato
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Sapna
S
Devi
Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC 3010, Australia.
Roghieh
R
Skandari
Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC 3010, Australia.
Michael
M
Pauley
Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC 3010, Australia.
Jonathan H
JH
Manton
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Dale I
DI
Godfrey
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Asolina
A
Braun
Liver Immunology Program, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Locked Bag No 6, Sydney, NSW 2042, Australia.
Szun Szun
SS
Tay
Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia.
Peck Szee
PS
Tan
Liver Immunology Program, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Locked Bag No 6, Sydney, NSW 2042, Australia.
David G
DG
Bowen
Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Friedrich
F
Koch-Nolte
Institute of Immunology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Björn
B
Rissiek
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia.
Francis R
FR
Carbone
Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia.
Brendan S
BS
Crabb
Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia.
Mireille
M
Lahoud
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
Ian A
IA
Cockburn
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
Scott N
SN
Mueller
Liver Immunology Program, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Locked Bag No 6, Sydney, NSW 2042, Australia.
Patrick
P
Bertolino
The School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia.
Geoffrey I
GI
McFadden
Macfarlane Burnet Institute for Medical Research & Public Health, Melbourne, VIC 3004, Australia; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia. Electronic address: irina.caminschi@monash.edu.au.
Irina
I
Caminschi
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, VIC 3010, Australia; The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: wrheath@unimelb.edu.au.
William R
WR
Heath
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D009033:Culicidae; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology; D022781:Hepatocytes / Q000276:immunology / Q000469:parasitology; D007156:Immunologic Memory / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000469:parasitology; D008107:Liver Diseases / Q000276:immunology / Q000469:parasitology; D008288:Malaria / Q000276:immunology*; D017780:Malaria Vaccines / Q000276:immunology; D051379:Mice; D010962:Plasmodium berghei / Q000276:immunology; D034101:Sporozoites / Q000276:immunology / Q000469:parasitology; D014611:Vaccination / Q000379:methods
D017780:Malaria Vaccines
CD8(+) T cells; Clec9A; liver; liver surveillance; malaria; memory T cells; sporozoite; tissue-resident memory; vaccine