title: 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.
abstract: 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.
authors: Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Karlhans Fru
authors: KF
authors: Che
authors: Esaki Muthu
authors: EM
authors: Shankar
authors: Sundaram
authors: S
authors: Muthu
authors: Sasan
authors: S
authors: Zandi
authors: Mikael
authors: M
authors: Sigvardsson
authors: Jorma
authors: J
authors: Hinkula
authors: Davorka
authors: D
authors: Messmer
authors: Marie
authors: M
authors: Larsson
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004768:Enterotoxins / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009500:Neutralization Tests; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004768:Enterotoxins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D048051:p38 Mitogen-Activated Protein Kinases