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p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
University of Malaya, Malaysia .
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, Vol. 18, no 8, 1169-1182 p.Article in journal (Refereed) Published
Abstract [en]

Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3). T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. Online address: doi: 10.2119/molmed.2012.00103

Place, publisher, year, edition, pages
Feinstein Institute for Medical Research , 2012. Vol. 18, no 8, 1169-1182 p.
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Medical and Health Sciences
URN: urn:nbn:se:liu:diva-87545DOI: 10.2119/molmed.2012.00103ISI: 000311067400003OAI: diva2:589611
Available from: 2013-01-18 Created: 2013-01-18 Last updated: 2013-02-04

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Che, Karlhans FruMuthu, SundaramZandi, SasanSigvardsson, MikaelHinkula, JormaLarsson, Marie
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Molecular VirologyFaculty of Health SciencesDepartment of Clinical and Experimental MedicineExperimental Hematology
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Molecular medicine (Cambridge, Mass. Print)
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