| 1. |
- Che, Karlhans Fru, et al.
(författare)
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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
- 2012
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Ingår i: Molecular Medicine. - : Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 18:8, s. 1169-1182
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Tidskriftsartikel (refereegranskat)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. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00103
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| 2. |
- Barathan, Muttiah, et al.
(författare)
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Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion
- 2018
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 7:10
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Forskningsöversikt (refereegranskat)abstract
- Hepatitis C virus (HCV) represents a challenging global health threat to similar to 200 million infected individuals. Clinical data suggest that only similar to 10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
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| 3. |
- Che, Karlhans Fru, et al.
(författare)
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Cross Talk between P38MAPK and STAT3 Regulates Expression of Negative Costimulatory Molecules and Transcriptional Repressors in HIV-1 Primed T cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 infection enhances the expression of negative costimulatory molecules on T cellsleading to T cell impairment. The signaling pathway underlying the regulation ofinhibitory molecules and the subsequent onset of T cell impairment remains to beinvestigated. Herein, we showed that the T cells activated by HIV-pulsed dendritic cells(DCs) upregulated CTLA-4, TRAIL, LAG-3, TIM-3, and CD160 and suppressionassociated transcription factors BLIMP-1, DTX1, and FOXP3, leading to T cellsuppression. The induction of suppressor T cells was regulated by the signal transducerand activator of transcription 3 (STAT3) molecules as blockade of this pathwaysignificantly down regulates the expression of inhibitory molecules. The cytokines IL-6and IL-10 were not responsible for STAT3 activation as their neutralization could neitherrecover T cell proliferation nor decrease the expression of negative costimulatorymolecules. Contrarily, we demonstrated that the intracytoplasmic cross-talk of P38Mitogen-Activated Protein Kinase (MAPK) with STAT3 was responsible as blockade ofthe P38MAPK significantly impaired negative costimulatory molecular expression andthe subsequent recovery of T cell proliferation. Notably, the blockade of viral access toDC cytosol, via CD4 binding and fusion, significantly reduced the negative effects DCsimposed on the primed T cells. In conclusion, viral access to cytosol modulated theDCs- T cell priming to induce T cells with upreguled expression of negativecostimulatory molecules in a P38MAPK/STAT3 pathway dependent fashion
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| 4. |
- Saeidi, Alireza, et al.
(författare)
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T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses
- 2018
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 9
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Forskningsöversikt (refereegranskat)abstract
- T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
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| 5. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Platelet-Large Cell Ratio and Erythrocyte Sedimentation Rate are Surrogate Predictors of Latent Tuberculosis Infection
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims: Prompt detection and treatment of latent tuberculosis infection (LTBI) holds the key to global TB elimination. The lack of an established test for predicting LTBI poses a substantial challenge in disease management. Here, we identified the biochemical and hematological markers of LTBI, and correlated their usefulness to discriminate LTBI from healthy controls. Main Methods: We conducted a cross-sectional investigation and correlated the various biochemical and hematological markers for detecting LTBI among household contacts (HHCs) of TB infection. Our study included 90 individuals – 30 healthy controls, 30 interferon-gamma release assay (IGRA) positive HHCs, and 30 IGRA-negative HHCs. Biomarkers were measured using designated auto analyzers. Key Findings: ESR, MPV, D-dimer, P-LCR, and PDW were significantly higher among LTBI subjects. ESR, PDW, and P-LCR were markedly associated with LTBI. Multivariate analysis showed that either ESR or P-LCR greater than their respective predetermined cut-off values showed higher odds of developing LTBI. Our study demonstrated that ESR and P-LCR are good surrogate markers for diagnosing LTBI. Also, significantly low ferritin in females and MCHC in males belonging to the HHC/IGRA-ve were observed. Significance: The ESR and P-LCR could aid in predicting LTBI among HHCs. Further, the low serum ferritin is associated with TB resisters.
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| 6. |
- Vimali, Jaisheela, et al.
(författare)
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HIV-HPgV Co-Infected Individuals Display Functional MAIT and Follicular T Cells Irrespective of PD-1 Expression
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Human Pegivirus (HPgV) appears to alter the clinical outcome of HIV disease by modulating T-cell homeostasis, chemokine/cytokine production, as well as by reducing T-cell activation, and proliferation to limit HIV replication. Here, we evaluated if HPgV had any ‘favorable’ impact on the quantity and quality of T cells in HIV-infected individuals. T-cell subsets such as CD4lo, CD4hi, and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells, follicular helper T cells (Tfh), and follicular cytotoxic T cells (Tfc) were characterized based on the expression of markers associated with immune activation (CD69, ICOS), proliferation (ki67), cytokine production (TNF-α, IFN-γ), and exhaustion (PD-1). HIV+HPgV+ individuals had lower plasma liver transaminase SGOT and GGT (biliary) than those who were HPgV-. HIV/HPgV co-infection was significantly associated with increased absolute CD4+ T-cell counts. HIV+HPgV+ and HIV+HPgV- individuals had highly activated T-cell subsets with high expression of CD69 and ICOS on bulk CD4+ and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells and CXCR5+CD4+ T cells and CXCR5+CD8+ T cells as compared to healthy controls. Irrespective of activation markers these cells also expressed higher levels of PD-1 on CD4+ T and CD8+ T cells and their counterparts. However, exploring their functionality based on the mitogen stimulation demonstrated higher levels of cytokine production by CD4+ MAIT and CD8+ MAIT cells as compared to healthy controls. Decrease in absolute CD4+ T cell counts correlated positively with intracellular IFN-γ levels by CD4lo T cells, whereas increase of the same correlated inversely with TNF-α in the CD4lo T cells of HIV+HPgV+ individuals. Together, we found that HIV/HPgV co-infected individuals display functional CD4+ and CD8+ MAIT, Tfh and Tfc cells irrespective of PD-1 expression.
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