| 1. |
- Abbafati, Cristiana, et al.
(författare)
-
- 2020
-
Tidskriftsartikel (refereegranskat)
|
|
| 2. |
- Saeidi, Alireza, et al.
(författare)
-
T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses
- 2018
-
Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 9
-
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.
|
|
| 3. |
- Barathan, Muttiah, et al.
(författare)
-
CD8+T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides
- 2017
-
Ingår i: Cellular Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0008-8749 .- 1090-2163. ; 313
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray (TM) following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-beta 1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-alpha, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence. (C) 2016 Elsevier Inc. All rights reserved.
|
|
| 4. |
- Barathan, Muttiah, et al.
(författare)
-
Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes
- 2015
-
Ingår i: Apoptosis (London). - : Springer Verlag (Germany). - 1360-8185 .- 1573-675X. ; 20:4, s. 466-480
-
Tidskriftsartikel (refereegranskat)abstract
- Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(A (R)) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.
|
|
| 5. |
- Barathan, Muttiah, et al.
(författare)
-
Hepatitis C virus infection contributes to impregnation of markers of immune inhibition : potential preludes underlying viral latency and persistence
- 2014
-
Ingår i: BMC Infectious Diseases. - : Springer Nature. - 1471-2334. ; 14:Suppl 3
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundHepatitis C virus (HCV) represents one of the persistent viral infections afflicting humankind, and a significant proportion of chronic HCV disease progresses over time through liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). One potential mechanism underlying the chronic disease is believed to be viral escape from immune surveillance via upregulation of inhibitory molecules on immune cells by HCV. We investigated the diverse expression of various inhibitory molecules in PBMCs of healthy non-HCV controls and chronically HCV infected patients.MethodsThe expression of inhibitory molecules on PBMCs was investigated in chronic HCV infected patients relative to healthy non-HCV controls using standard immunological and molecular methods. The serum levels of indoleamine 2, 3 deoxygenase (IDO) and cyclooxygenase-2 (COX-2) were also investigated.ResultsThe gene expression profile of chronically HCV infected patients was significantly different from control individuals. Our results showed upregulation of TIM-3 (p≤0.01), PD-1 (p≤0.01), FOXP-3 (p≤0.01), BLIMP-1 (p≤0.01), CD160 (p≤0.01), CTLA-4 (p≤0.01), TRAIL (p≤0.01), BTLA (p≤0.01) and LAG-3 (p≤0.01) with fold change of 1.3, 0.4, 14.6, 0.87, 6.6, 0.4, 14.7, 10.9 and 2.5 respectively in chronically HCV infected patients. The plasma IDO and COX-2 levels were significantly higher (p=0.001) in chronically HCV infected subjects relative to healthy control.ConclusionThe upregulation of inhibitory molecules on PBMCs in chronically HCV infected patients suggest the contribution of these molecules to immune cells impairment in HCV infection. Viral persistence and eventual progression following potential evasion of the host immune armory via viral impregnation of inhibitory immune biosignatures in HCV disease pathogenesis warrants further elucidation.
|
|
| 6. |
- Barathan, Muttiah, et al.
(författare)
-
Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease
- 2015
-
Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 45:5, s. 466-474
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundHepatitis C virus (HCV) causes persistent disease in similar to 85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. Materials and methodsWe characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 (IL-7R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. ResultsHCV-specific CD4+ and CD8+ T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. ConclusionsChronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection.
|
|
| 7. |
- Barathan, Muttiah, et al.
(författare)
-
Peripheral loss of CD8(+)CD161(++)TCRV7 center dot 2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients
- 2016
-
Ingår i: European Journal of Clinical Investigation. - : WILEY-BLACKWELL. - 0014-2972 .- 1365-2362. ; 46:2, s. 170-180
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundMucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. Materials and methodsWe investigated the frequency of CD8(+)CD161(++)TCR V7.2(+) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. ResultsThe frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. ConclusionsImmune exhaustion and senescence of CD8(+)CD161(++)TCR V7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.
|
|
| 8. |
- Barathan, Muttiah, et al.
(författare)
-
Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion
- 2018
-
Ingår i: Cells. - : MDPI. - 2073-4409. ; 7:10
-
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.
|
|
| 9. |
- Larsson, Marie, et al.
(författare)
-
Molecular signatures of T-cell inhibition in HIV-1 infection
- 2013
-
Ingår i: Retrovirology. - : BioMed Central. - 1742-4690. ; 10:1
-
Forskningsöversikt (refereegranskat)abstract
- Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection.
|
|
| 10. |
- Saeidi, Alireza, et al.
(författare)
-
Attrition of TCR Va7.2+CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression
- 2015
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:4, s. e0124659-
-
Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8+ T cells co-expressing the semi-invariant TCR V alpha 7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161++ CD8+ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naive HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naive HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono-and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono-and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.
|
|
