Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

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Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽

10.1371/journal.pone.0254243 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254243

Author(s):

Meritxell Llorens-Revull ◽

Maria Isabel Costafreda ◽

Angie Rico ◽

Mercedes Guerrero-Murillo ◽

Maria Eugenia Soria ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Hepatitis C ◽

T Cell ◽

Cd8 T Cells ◽

Viral Clearance ◽

Cd4 T Cell ◽

Care Hospital ◽

T Cell Exhaustion ◽

Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

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DHX37 Impacts Prognosis of Hepatocellular Carcinoma and Lung Adenocarcinoma through Immune Infiltration

Journal of Immunology Research ◽

10.1155/2020/8835393 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20

Author(s):

Yanni Xu ◽

Qiongchao Jiang ◽

Hejun Liu ◽

Xiaoyun Xiao ◽

Dinghong Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Lung Adenocarcinoma ◽

Immune Tolerance ◽

Prognostic Value ◽

Complex Function ◽

T Cell Exhaustion ◽

Rna Helicases ◽

Cell Exhaustion

Background. RNA helicases have various essential functions in basically all aspects of RNA metabolism, not only unwinding RNA but also disturbing the interaction of RNA with proteins. Recently, RNA helicases have been considered potential targets in cancers. So far, there has been no detailed investigation of the biological functions of RNA helicase DHX37 in cancers. Objective. We aim to identify the prognostic value of DHX37 associated with tumor microenvironments in cancers. Methods. DHX37 expression was examined via the Oncomine database and Tumor Immune Estimation Resource (TIMER). We explored the prognostic role of DHX37 in cancers across various databases. Coexpression genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and fundamental regulators were performed via LinkedOmics. Confirming the prognostic value of DHX37 in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD), we explored the role of DHX37 in infiltrated lymphocytes in cancers using the Gene Expression Profiling Interactive Analysis (GEPIA) and TIMER databases. Results. Through GO and KEGG analyses, expression of DHX37 was also correlated with complex function-specific networks involving the ribosome and RNA metabolic signaling pathways. In LIHC and LUAD, DHX37 expression showed significant positive correlations with markers of Tregs, myeloid-derived suppressor cells (MDSCs), and T cell exhaustion, contributing to immune tolerance. Conclusion. These results indicate that DHX37 can serve as a prognostic biomarker in LIHC and LUAD while having an important role in immune tolerance by activating the function of Tregs, MDSC, and T cell exhaustion.

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VitaminD3 Regulates T Cell Immune Responses in Allergen and Rhinovirus Induced Asthma

10.21203/rs.3.rs-289750/v1 ◽

2021 ◽

Author(s):

Susetta Finotto ◽

Patricia Haag ◽

Darja Andreev ◽

Nina Li ◽

Alexander Kiefer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Murine Model ◽

Peripheral Blood ◽

Serum Levels ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Asthmatic Children ◽

Rhinovirus Infection

Abstract Background: Serum 25(OH)-Vitamin D3 (VitD3) deficiency during infancy has been associated with asthma. The potential therapeutic role of VitD3 given in the airways and its interference with the allergen and Rhinovirus was the objective of this study. Methods: In two cohorts of children with and without asthma, serum levels of the C-reactive protein (CRP) were correlated to Serum VitD3 and in peripheral blood T cell inhibitor marker Programmed cell death protein 1 (PD1) mRNA was analyzed. In a murine model, VitD3 was given intranasally in vivo and in vitro to lung cells with allergen and Rhinovirus. Results: In the cohorts of pre-school age children without (control) asthma, CRP and VitD3 levels inversely correlated. In preschool asthmatic children that did not receive VitD3 supplementation as infant had more episode of asthma exacerbation associated with high CRP serum level. In peripheral blood cells from control but not asthmatic children with higher serum levels of VitD3 had lower PD1 mRNA levels. In murine model, OVA intranasal challenge induced Innate Lymphoid Cells type 2 (ILC2)-associated markers and Eosinophils in BALF and VitD3 inhibited lung inflammation and ILC2 markers. Furthermore, VitD3 given intranasally, induced CD4+T cells and reduced PD1, T regulatory cells in the lung. Similarly, VitD3 had a suppressive role on CD4+PD1+ T cells involved in T cell exhaustion in the airways in the absence of ST2 after Rhinovirus infection. Conclusion: These data support an inhibitory role of VitD3 on T cell exhaustion after allergen and rhinovirus infection that is relevant for pediatric asthma.

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PS-103-BTLA expression contributes to HBV-related acute-on-chronic liver failure morbidity and mortality by inducing CD4+ T-cell exhaustion

Journal of Hepatology ◽

10.1016/s0618-8278(19)30115-x ◽

2019 ◽

Vol 70 (1) ◽

pp. e65-e66

Author(s):

Xueping Yu ◽

Feifei Yang ◽

Richeng Mao ◽

Haoxiang Zhu ◽

Qirong Jiang ◽

...

Keyword(s):

T Cell ◽

Liver Failure ◽

Chronic Liver ◽

Morbidity And Mortality ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Chronic Liver Failure ◽

Cell Exhaustion

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Short Communication: Metformin Reduces CD4 T Cell Exhaustion in HIV-Infected Adults on Suppressive Antiretroviral Therapy

AIDS Research and Human Retroviruses ◽

10.1089/aid.2019.0078 ◽

2020 ◽

Vol 36 (4) ◽

pp. 303-305 ◽

Cited By ~ 8

Author(s):

Cecilia M. Shikuma ◽

Glen M. Chew ◽

Lindsay Kohorn ◽

Scott A. Souza ◽

Dominic Chow ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Short Communication ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion

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Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

10.21203/rs.3.rs-475376/v1 ◽

2021 ◽

Author(s):

Yini Sun ◽

Renyu Ding ◽

Yukun Chang ◽

Jiuming Li ◽

Xiaochun Ma

Keyword(s):

T Cells ◽

T Cell ◽

Crucial Role ◽

Cell Function ◽

Inflammatory Responses ◽

Ex Vivo ◽

Healthy Controls ◽

T Cell Exhaustion ◽

Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

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No evidence for CD4+ T-cell ‘exhaustion’ in HIV infection

Immunology Today ◽

10.1016/s0167-5699(97)84241-7 ◽

1997 ◽

Vol 18 (2) ◽

pp. 55

Keyword(s):

T Cell ◽

Hiv Infection ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion

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Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-β Levels in Treated HIV+ Immune Non-responders

Frontiers in Immunology ◽

10.3389/fimmu.2021.638010 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carey L. Shive ◽

Michael L. Freeman ◽

Souheil-Antoine Younes ◽

Corinne M. Kowal ◽

David H. Canaday ◽

...

Keyword(s):

T Cell ◽

Plasma Levels ◽

T Regulatory Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Regulatory Cells ◽

Cell Exhaustion ◽

Immune Mediators ◽

T Cell Senescence

Background: Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age.Methods: Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-β and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts (n = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; n = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics.Results: Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-β levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-β negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets.Conclusions: INR have lower levels of TGF-β and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.

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