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

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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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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Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection

PLoS ONE ◽

10.1371/journal.pone.0193829 ◽

2018 ◽

Vol 13 (3) ◽

pp. e0193829 ◽

Cited By ~ 11

Author(s):

Norma Rallón ◽

Marcial García ◽

Javier García-Samaniego ◽

Alfonso Cabello ◽

Beatriz Álvarez ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

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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CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

Cell Reports ◽

10.1016/j.celrep.2021.109696 ◽

2021 ◽

Vol 36 (11) ◽

pp. 109696

Author(s):

Yu-Jung Lu ◽

Palmira Barreira-Silva ◽

Shayla Boyce ◽

Jennifer Powers ◽

Kelly Cavallo ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

T Cell ◽

Cd8 T Cell ◽

Tuberculosis Infection ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Mycobacterium Tuberculosis Infection ◽

Cell Exhaustion ◽

Cd4 T Cell Help ◽

T Cell Help

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CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis

PLoS ONE ◽

10.1371/journal.pone.0188882 ◽

2017 ◽

Vol 12 (12) ◽

pp. e0188882 ◽

Cited By ~ 6

Author(s):

Kimberly M. Ramonell ◽

Wenxiao Zhang ◽

Annette Hadley ◽

Ching-wen Chen ◽

Katherine T. Fay ◽

...

Keyword(s):

T Cell ◽

Murine Model ◽

Polymicrobial Sepsis ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion

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Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

Journal of Experimental Medicine ◽

10.1084/jem.20151995 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1799-1818 ◽

Cited By ~ 35

Author(s):

SuJin Hwang ◽

Dustin A. Cobb ◽

Rajarshi Bhadra ◽

Ben Youngblood ◽

Imtiaz A. Khan

Keyword(s):

T Cells ◽

T Cell ◽

Critical Role ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Cell Dysfunction ◽

T Cell Dysfunction

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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