Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1002504
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dc.titleThe CTLA-4 and PD-1/PD-l1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology
dc.contributor.authorHafalla J.C.R.
dc.contributor.authorClaser C.
dc.contributor.authorCouper K.N.
dc.contributor.authorGrau G.E.
dc.contributor.authorRenia L.
dc.contributor.authorde Souza J.B.
dc.contributor.authorRiley E.M.
dc.date.accessioned2020-03-13T05:26:14Z
dc.date.available2020-03-13T05:26:14Z
dc.date.issued2012
dc.identifier.citationHafalla 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
dc.identifier.issn15537366
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/165409
dc.description.abstractThe 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.
dc.publisherPublic Library of Science
dc.sourceUnpaywall 20200320
dc.subjectcytotoxic T lymphocyte antigen 4
dc.subjectgamma interferon
dc.subjectprogrammed death 1 ligand 1
dc.subjectCd274 protein, mouse
dc.subjectcytotoxic T lymphocyte antigen 4
dc.subjectdifferentiation antigen
dc.subjectgamma interferon
dc.subjectPD 1 antigen, mouse
dc.subjectPD-1 antigen, mouse
dc.subjectprogrammed death 1 ligand 1
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectarticle
dc.subjectBagg albino mouse
dc.subjectbrain malaria
dc.subjectC57BL 6 mouse
dc.subjectCD8+ T lymphocyte
dc.subjectcontrolled study
dc.subjecthomeostasis
dc.subjecthost resistance
dc.subjectimmune response
dc.subjectlymphocyte depletion
dc.subjectmouse
dc.subjectnonhuman
dc.subjectPlasmodium berghei infection
dc.subjectprotein expression
dc.subjectT lymphocyte activation
dc.subjectanimal
dc.subjectC57BL mouse
dc.subjectCD8+ T lymphocyte
dc.subjecterythrocyte
dc.subjectimmunology
dc.subjectlymphocyte activation
dc.subjectmalaria
dc.subjectmetabolism
dc.subjectmicrobiology
dc.subjectparasitology
dc.subjectpathogenicity
dc.subjectpathology
dc.subjectPlasmodium berghei
dc.subjectMus
dc.subjectPlasmodium berghei
dc.subjectAnimals
dc.subjectAntigens, CD274
dc.subjectAntigens, Differentiation
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectCTLA-4 Antigen
dc.subjectErythrocytes
dc.subjectInterferon-gamma
dc.subjectLymphocyte Activation
dc.subjectMalaria, Cerebral
dc.subjectMice
dc.subjectMice, Inbred BALB C
dc.subjectMice, Inbred C57BL
dc.subjectPlasmodium berghei
dc.typeArticle
dc.contributor.departmentMICROBIOLOGY AND IMMUNOLOGY
dc.description.doi10.1371/journal.ppat.1002504
dc.description.sourcetitlePLoS Pathogens
dc.description.volume8
dc.description.issue2
dc.description.pagee1002504
dc.published.statePublished
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