Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection

Shahbaz, Shima; Dunsmore, Garett; Koleva, Petya; Xu, Lai; Houston, Stan; Elahi, Shokrollah

doi:10.4049/jimmunol.1901481

Cited by 52 publications

(66 citation statements)

References 100 publications

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“…This observation raised additional questions regarding impaired HIV-specific CD8 + T cell proliferation in patients with HLA-B*35Px. To address this question, we speculated that chronic HIV infection results in the upregulation of other co-inhibitory receptors and subsequently CTL exhaustion[ 41 ]. We have previously shown that NK cells and CTLs upon chronic HIV-1 antigenic stimulation upregulate various co-inhibitory receptors such as PD-1, CTLA-4, TIM-3, 2B4, CD160, Gal-9, CD39, and VISTA [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

2020

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HLA-B*35Px is associated with HIV-1 disease rapid progression to AIDS. However, the mechanism(s) underlying this deleterious effect of this HLA allele on HIV-1 infection outcome has not fully understood. CD8 + T cells play a crucial role to control the viral replication but impaired CD8 + T cells represent a major hallmark of HIV-1 infection. Here, we examined the effector functions of CD8 + T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02), HLA-B*27/B57 and non-HLA-B*27/B57 (e.g. HLA-A*01, A*02, A*03, A*11, A*24, A*26, B*40, B*08, B*38, B*44). CD8 + T cells restricted by HLA-B*35Px exhibited an impaired phenotype compared with those restricted by HLA-B*27/B57 and even non-HLA-B*27/B57. CD8 + T cells restricted by non-HLA-B*27/B57 when encountered their cognate epitopes upregulated TIM-3 and thus became suppressed by regulatory T cells (Tregs) via TIM-3: Galectin-9 (Gal-9). Strikingly, CD8 + T cells restricted by HLA-B*35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8 + T cells restricted by HLA-B*27/B57. Instead, CD8 + T cells restricted by HLA-B*35Px upon recognition of their cognate epitopes upregulated CTLA-4. The transcriptional and impaired phenotype (e.g. poor effector functions) of HIV-specific CD8 + T cells restricted by HLA-B*35 was related to persistent CTLA-4, elevated Eomes and blimp-1 but poor T-bet expression. As such, anti-CTLA-4 antibody, Ipilimumab, reversed the impaired proliferative capacity of antigen-specific CD8 + T cells restricted by HLA-B*35Px but not others. This study supports the concept that CD8 + T resistance to Tregs-mediated suppression is related to allele restriction rather than the epitope specificity. Our results aid to explain a novel mechanism for the inability of HIV-specific CD8 + T cells restricted by HLA-B*35Px to control viral replication.

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Section: Discussionmentioning

confidence: 99%

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

2020

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“…For example, in the context of infection, cancer or transplantation, chronic exposure to antigen leads to a phenomenon termed exhaustion, characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucindomain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3), diminished proliferative and cytokine-producing capacity, and high apoptosis (Fribourg et al, 2019;Saeidi et al, 2018;Thorp et al, 2015;Wherry and Kurachi, 2015). Although most research in this area examined effects on CD8 + T cells or unfractionated CD3 + T cells, but there is evidence that CD4 + T cells are similarly susceptible to exhaustion Shahbaz et al, 2020;Zou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion

Lamarche

Novakovsky

et al. 2020

Preprint

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Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. We studied how two methods which induce conventional T cell exhaustion -repetitive stimulation or expression of a tonic-signaling chimeric antigen receptor (CAR) -affect human Tregs. With each repetitive polyclonal stimulation Tregs progressively acquired an exhausted phenotype, and became less suppressive in vitro. Tregs expressing a tonic-signaling CAR rapidly acquired an exhausted phenotype and had major changes in their transcriptome and metabolism. Although tonicsignaling CAR-Tregs remained stable and suppressive in vitro, they lost in vivo function, as tested in a model of xenogeneic graft-versus-host disease. The finding that human Tregs are susceptible to exhaustion has important implications for the design of Treg adoptive immunotherapy strategies.

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“…HIV-infected individuals on ART were shown to exhibit significantly higher Gal-9 expression on both CD4+ and CD8+ T cells compared with ART naïve patients and long term non-progressors (LTNPs) indicating presence of generalized hyperimmune activation in HIV patients despite ART (Shahbaz et al, 2020). It was also reported that the expression of Gal-9 and Tim3 molecules was upregulated during an Mtb infection and that Gal-9/Tim3 pathway was necessary to activate bactericidal mechanisms to control intracellular bacterial growth (Jayaraman et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals

et al. 2020

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Galectin-9 (Gal-9) and osteopontin (OPN) play immunomodulatory roles in tuberculosis and HIV infections. Evaluation of their levels as well as their interplay with different pro-inflammatory cytokines is critical to understand their role in immunopathogenesis of HIV/tuberculosis co-infection considering the complexity of the disease. Plasma levels of these proteins were measured by ELISAs in HIV-negative individuals with pulmonary (n = 21), extrapulmonary (n = 33), and latent tuberculosis (n = 22) and in HIV infected patients with pulmonary (n = 14), latent tuberculosis (n = 17), and without tuberculosis (n = 41). Levels of pro-inflammatory cytokines were estimated by Luminex assay. Receiver operated characteristic curve analysis was performed to evaluate discriminatory roles of these proteins. Spearman's correlation analysis was performed with the markers of HIV and tuberculosis disease progression to evaluate their immunopathogenic roles. Gal-9 and OPN levels were higher in HIV uninfected patients with active tuberculosis than with latent tuberculosis. Gal-9 but not OPN levels were higher in HIV infected patients with active tuberculosis than with latent tuberculosis. Area under curve for Galectin-9 was >0.9 in HIV/tuberculosis coinfection and extrapulmonary tuberculosis. OPN and IL-6 levels were higher in patients with severe chest X-ray grade indicating its association with severity of the disease and positively correlated with each other. Stronger positive and negative correlations of Gal-9 levels, respectively, with viral loads and CD4 cell counts in HIV infected patients were observed than OPN levels indicating their association with HIV disease progression. Thus, significantly elevated Gal-9 levels were reported for the first time in HIV/tuberculosis co-infection and extrapulmonary tuberculosis in our study than single infections with HIV and tuberculosis. The study indicated a need for further evaluation of monitoring role of Gal-9 for detection of developing tuberculosis in HIV infected individuals. The findings also indicated differential roles of Gal-9 and OPN in the pathogenesis of tuberculosis and HIV infections.

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Galectin-9 and VISTA Expression Define Terminally Exhausted T Cells in HIV-1 Infection

Cited by 52 publications

References 100 publications

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

Repeated stimulation or tonic-signaling chimeric antigen receptors drive regulatory T cell exhaustion

Elevated Levels of Galectin-9 but Not Osteopontin in HIV and Tuberculosis Infections Indicate Their Roles in Detecting MTB Infection in HIV Infected Individuals

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