Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1002504
Title: The CTLA-4 and PD-1/PD-l1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology
Authors: Hafalla J.C.R.
Claser C.
Couper K.N.
Grau G.E.
Renia L. 
de Souza J.B.
Riley E.M.
Keywords: cytotoxic T lymphocyte antigen 4
gamma interferon
programmed death 1 ligand 1
Cd274 protein, mouse
cytotoxic T lymphocyte antigen 4
differentiation antigen
gamma interferon
PD 1 antigen, mouse
PD-1 antigen, mouse
programmed death 1 ligand 1
animal cell
animal experiment
animal model
animal tissue
article
Bagg albino mouse
brain malaria
C57BL 6 mouse
CD8+ T lymphocyte
controlled study
homeostasis
host resistance
immune response
lymphocyte depletion
mouse
nonhuman
Plasmodium berghei infection
protein expression
T lymphocyte activation
animal
C57BL mouse
CD8+ T lymphocyte
erythrocyte
immunology
lymphocyte activation
malaria
metabolism
microbiology
parasitology
pathogenicity
pathology
Plasmodium berghei
Mus
Plasmodium berghei
Animals
Antigens, CD274
Antigens, Differentiation
CD8-Positive T-Lymphocytes
CTLA-4 Antigen
Erythrocytes
Interferon-gamma
Lymphocyte Activation
Malaria, Cerebral
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Plasmodium berghei
Issue Date: 2012
Publisher: Public Library of Science
Citation: Hafalla J.C.R., Claser C., Couper K.N., Grau G.E., Renia L., de Souza J.B., Riley E.M. (2012). The CTLA-4 and PD-1/PD-l1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology. PLoS Pathogens 8 (2) : e1002504. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1002504
Abstract: The balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of microbial infections. This balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L, which dampen effector responses during chronic infections. However, their role in acute infections, such as malaria, remains less clear. In this study, we determined the contribution of CTLA-4 and PD-1/PD-L to the regulation of T cell responses during Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM) in susceptible (C57BL/6) and resistant (BALB/c) mice. We found that the expression of CTLA-4 and PD-1 on T cells correlates with the extent of pro-inflammatory responses induced during PbA infection, being higher in C57BL/6 than in BALB/c mice. Thus, ECM develops despite high levels of expression of these inhibitory receptors. However, antibody-mediated blockade of either the CTLA-4 or PD-1/PD-L1, but not the PD-1/PD-L2, pathways during PbA-infection in ECM-resistant BALB/c mice resulted in higher levels of T cell activation, enhanced IFN-? production, increased intravascular arrest of both parasitised erythrocytes and CD8+ T cells to the brain, and augmented incidence of ECM. Thus, in ECM-resistant BALB/c mice, CTLA-4 and PD-1/PD-L1 represent essential, independent and non-redundant pathways for maintaining T cell homeostasis during a virulent malaria infection. Moreover, neutralisation of IFN-? or depletion of CD8+ T cells during PbA infection was shown to reverse the pathologic effects of regulatory pathway blockade, highlighting that the aetiology of ECM in the BALB/c mice is similar to that in C57BL/6 mice. In summary, our results underscore the differential and complex regulation that governs immune responses to malaria parasites. © 2012 Hafalla, et al.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/165409
ISSN: 15537366
DOI: 10.1371/journal.ppat.1002504
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