title: Expression of a broad array of negative costimulatory molecules and Blimp-1 in T cells following priming by HIV-1 pulsed dendritic cells.
abstract: Accumulating evidence indicates that immune impairment in persistent viral infections could lead to T-cell exhaustion. To evaluate the potential contribution of induction of negative costimulatory molecules to impaired T-cell responses, we primed naïve T cells with mature monocyte-derived dendritic cells (MDDCs) pulsed with HIV-1 in vitro. We used quantitative real-time polymerase chain reaction and flow cytometry, respectively, to compare the gene and surface-protein expression profiles of naïve T cells primed with HIV-pulsed or mock-pulsed DCs. We detected elevated expressions of negative costimulatory molecules, including lymphocyte activation gene-3 (LAG-3), CD160, cytolytic T-lymphocyte antigen-4 (CTLA-4), T-cell immunoglobulin mucin-containing domain-3 (TIM-3), programmed death-1 (PD-1) and TRAIL (tumor necrosis-factor-related apoptosis-inducing ligand) in T cells primed by HIV-pulsed DCs. The PD-1(+) T-cell population also coexpressed TIM-3, LAG-3, and CTLA-4. Interestingly, we also found an increase in gene expression of the transcriptional repressors Blimp-1 (B-lymphocyte-induced maturation protein-1) and Foxp3 (forkhead transcription factor) in T-cells primed by HIV-pulsed DCs; Blimp-1 expression was directly proportional to the expression of the negative costimulatory molecules. Furthermore, levels of the effector cytokines interleukin-2, tumor necrosis factor-α and interferon-γ, and perforin and granzyme B were decreased in T-cell populations primed by HIV-pulsed DCs. In conclusion, in vitro priming of naïve T-cells with HIV-pulsed DC leads to expansion of T cells with coexpression of a broad array of negative costimulatory molecules and Blimp-1, with potential deleterious consequences for T-cell responses.
authors.affiliation: Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. esakimuthu.shankar@liu.se
authors.forename: Esaki Muthu
authors.initials: EM
authors.lastname: Shankar
authors.forename: Karlhans Fru
authors.initials: KF
authors.lastname: Che
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015497:HIV-1 / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C114505:CD160 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007376:Interleukin-2; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C087042:PRDM1 protein, human; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000093322:Lymphocyte Activation Gene 3 Protein