Cutting edge: selective blockade of LIGHT-lymphotoxin beta receptor signaling protects mice from experimental cerebral malaria caused by Plasmodium berghei ANKA.
Studies in experimental cerebral malaria (ECM) in mice have identified T cells and TNF family members as critical mediators of pathology. In this study we report a role for LIGHT-lymphotoxin beta Receptor (LTbetaR) signaling in the development of ECM and control of parasite growth. Specific blockade of LIGHT-LTbetaR, but not LIGHT-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic CD8(+) T cells and monocytes to the brain during infection without affecting early activation of CD4(+) T cells, CD8(+) T cells, or NK cells. Importantly, blockade of LIGHT-LTbetaR signaling caused the expansion of splenic monocytes and an overall enhanced capacity to remove and process Ag during infection, as well as reduced systemic cytokine levels when control mice displayed severe ECM symptoms. In summary, we have discovered a novel pathogenic role for LIGHT and LTbetaR in ECM, identifying this TNF family receptor-ligand interaction as an important immune regulator during experimental malaria.
Randall
Louise M
LM
Queensland Institute of Medical Research, Herston, Queensland, Australia.
Amante
Fiona H
FH
Zhou
Yonghong
Y
Stanley
Amanda C
AC
Haque
Ashraful
A
Rivera
Fabian
F
Pfeffer
Klaus
K
Scheu
Stefanie
S
Hill
Geoff R
GR
Tamada
Koji
K
Engwerda
Christian R
CR
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D001921:Brain / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology*; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000276:immunology*
D000953:Antigens, Protozoan; D016207:Cytokines; D053259:Lymphotoxin beta Receptor; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14