Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8+ T cells in HIV/TB co-infection

Saeidi, Alireza; Chong, Yee Kien; Yong, Yean Kong; Tan, Hui; Barathan, Muttiah; Jayakumar, R.; Sabet, Negar Shafiei; Sekaran, Shamala Devi; Ponnampalavanar, Sasheela; Karlhans, F.; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie; Shankar, Esaki Muthu

doi:10.1016/j.cellimm.2015.05.005

Cited by 12 publications

(9 citation statements)

References 46 publications

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“…MAIT cells express a semi-invariant T cell receptor (TCR), including Vα7.2 coupled with restricted Jα segments (Jα33, Jα12, or Jα20), and limited Vβ repertoires ( 20 , 21 ) as well as their high expression of CD161 ( 17 , 22 ). MAIT cells play an important role in innate host defense against bacterial infections and are either depleted and/or exhausted in chronic viral infections, including HIV ( 23 – 25 ), chronic HBV ( 26 ), and HCV infection ( 22 , 27 , 28 ), and TB infection ( 29 , 30 ). Here, we investigated the frequency and functional role of MAIT cells along with those of CD4 + and CD8 + T cells in chronic HBV infection.…”

Section: Introductionmentioning

confidence: 99%

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

et al. 2018

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Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.

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Section: Introductionmentioning

confidence: 99%

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

et al. 2018

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“…Conversely, at the opposite end of the spectrum, active TB in the setting of HIV co-infection represents a manifest failure of MTB resistance control characterised by bacillary dissemination, high bacterial load and higher mortality. Cellular immune responses that specifically characterise this state, including cellular senescence [ 6 ] or immune exhaustion phenotypes, may provide insight into cellular mechanisms of failed MTB-specific immunity. MTB-specific cell subsets that are preferentially impaired or depleted by HIV infection are therefore candidates for correlation of immune containment and protective immunity.…”

Section: Introductionmentioning

confidence: 99%

PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection

et al. 2016

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HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.

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“…Along with our observed impaired CD4 T cell response during coinfection (Paper II), the CD8 T cell response has also been shown to be affected. TB and HIV coinfected patients display an absence of co-stimulatory molecules and cytokine secretion in CD8 T cells, along with diminished levels of intracellular IFN-γ, perforin and granzyme B in HIV specific CD8 T cells (232). Thus, HIV does not only impair the CD4 T cell response against Mtb, but also during coinfection reduces the CD8 T cell response against the virus.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response

Andersson

2019

Linköping University Medical Dissertations

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Tuberculosis (TB) still remains a big threat today, being the leading cause of death by a single infectious agent. The TB epidemic is fueled by HIV along with the increasing drug-resistance which prolongs the already long treatment duration and decreases the success rate for curing TB. In most cases an infection results in latency but HIV patients have a 20-30 times higher risk of developing active TB. There are around 36.9 million people living with HIV globally, with the highest burden in Africa. Although there are effective treatments against the disease, there is no cure for AIDS and the availability of the lifelong treatment is limited in low-income countries were the burden is highest. HIV infection causes an immunodeficiency characterized by the progressive loss of CD4 T cells which increases the risk of opportunistic infections, and infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb spreads through aerosols from one person with active tuberculosis to a healthy person. Upon inhalation the bacteria are phagocytosed by alveolar macrophages that secrete cytokines and chemokines to recruit more cells, such as dendritic cells, macrophages and lymphocytes, leading to the formation of a granuloma. During a single TB infection the bacteria are usually contained within the granuloma, but HIV can disrupt the stable granuloma, causing a rupture and dissemination of Mtb. This inflammatory site is also beneficial to HIV since it promotes replication of the virus within infected cells. HIV and Mtb are two successful intracellular pathogens able to avoid immune defense mechanisms both of the innate and adaptive immunity in order to persist and replicate. Their virulence factors can manipulate or inhibit cell signaling, phagosome maturation, autophagy, ROS production, apoptosis and antigen presentation, to promote survival. Boosting of immune defenses with host-directed therapies (HDT) has been proposed as a treatment strategy against TB, either alone or adjunctive to the current regimen.

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Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8+ T cells in HIV/TB co-infection

Cited by 12 publications

References 46 publications

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection

Mycobacterium tuberculosis and HIV coinfection : Effects on innate immunity and strategies to boost the immune response

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