Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection

Kim, Kyle; Perera, Rebecca; Tan, Dino B.A.; Fernández, Sonia; Seddiki, Nabila; Waring, Justin; French, Martyn A.

doi:10.1016/j.tube.2014.07.002

Cited by 25 publications

(19 citation statements)

References 50 publications

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“…We reveal that the majority of circulating Mtb-specific CD4+ T cells appeared functional, as the frequency of cytokine-producing cells reflected the frequency of tetramer+ cells, and was comparable, regardless of HIV infection or active TB disease. We did not observe functional differences between LTBI and aTB, consistent with previous reports (41–44). This may be due to a limited number of participants analyzed in this study and CD4 responses to a single peptide not being representative of the response to the whole pathogen.…”

Section: Discussionsupporting

confidence: 93%

Characterization of Mycobacterium tuberculosis–Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease

Strickland

Müller

Berkowitz

et al. 2017

The Journal of Immunology

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A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4+ T cell responses are still elusive for human TB. Infection with human immunodeficiency virus-1 (HIV-1) is a major risk factor for tuberculosis (TB), and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. Eighty-six participants from a TB-endemic setting, either HIV-infected or -uninfected and with latent or active TB, were screened using Mtb-specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo Mtb-specific tetramer+CD4+ T cells using flow cytometry. The numbers of Mtb-specific tetramer+CD4+ T cells were relatively well maintained in HIV-infected persons with active TB, despite severe immunodeficiency. However, while HIV-uninfected persons with latent TB infection exhibited ex vivo Mtb-specific CD4+ T cells predominantly of a CXCR3+CCR6+CCR4- (Th1*) phenotype; active TB or HIV infection was associated with a contraction of this subset. Nevertheless, in individuals with active TB and/or HIV infection, circulating ex vivo Mtb-specific CD4+ T cells did not display defects in exhaustion or polyfunctionality compared to healthy HIV-uninfected individuals with latent TB infection. Collectively, these data suggest that increased susceptibility to TB disease could be related to a loss of circulating Th1* CD4+ T cells rather than major changes in the number or function of circulating CD4+ T cells.

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Section: Discussionsupporting

confidence: 93%

Characterization of Mycobacterium tuberculosis–Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease

Strickland

Müller

Berkowitz

et al. 2017

The Journal of Immunology

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“…Circulating antigen-reactive CD4 + T-cells expressing CD39 were also increased in patients with active rather than latent tuberculosis [17]. There is growing evidence to suggest that CD39 inhibits IFNγ production.…”

Section: Discussionmentioning

confidence: 95%

An evaluation of CD39 as a novel immunoregulatory mechanism invoked by COPD

et al. 2016

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Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are characterized by increased pulmonary and systemic inflammation and commonly caused by bacterial and/or viral infection. Little is known about the T-cell dysregulation in AECOPD that promotes these outcomes.CD39 is an ectonucleotidase able to hydrolyse adenosine triphosphate to create adenosine that may inhibit T-cell responses in patients with AECOPD. Here T-cell expression of CD39 measured by flow cytometry was higher in AECOPD patients than stable COPD patients or healthy controls. Higher expression of CD39 was associated with higher levels of plasma soluble tumor necrosis factor receptor but lower interferon-γ (IFNγ) levels in supernatants from staphylococcal enterotoxin-B stimulated peripheral blood mononuclear cells. This links increased expression of CD39 with systemic inflammation and impaired T-cell responses (e.g. IFNγ). The blockade of CD39 pathways may be a novel approach to the control of AECOPD, reducing the dependency on antibiotics.

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“…However, IFN-α-producing plasmacytoid dendritic cells seem to be of minor significance in TB patients (325, 327), and preclinical studies show that Mtb preferentially induces IFN-β through cytoplasmic pattern recognition receptors and IRF3 instead of IFN-α through endosomal toll-like receptors and IRF7 (79–81). Mycobacterial persistence in patients with TB is a major clinical problem and in line with the immunosuppressed state in active TB primarily supports a role for IFN-β (178, 333). However, exaggerated innate responses are also observed in TB where IFN-α might be involved.…”

Section: Interactions Between T1-ifns and Th17 Immunity In Tbmentioning

confidence: 96%

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

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The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.

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Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection

Abstract: Antigen-reactive CD4+ T cells expressing CD39 are more abundant in active TB than LTBI and are associated with production of the immunosuppressive cytokine IL-10. Modulating the effects of CD39 might enhance cellular immune responses against M. tuberculosis.

Cited by 25 publications

References 50 publications

Characterization of Mycobacterium tuberculosis–Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease

Characterization of Mycobacterium tuberculosis–Specific Cells Using MHC Class II Tetramers Reveals Phenotypic Differences Related to HIV Infection and Tuberculosis Disease

An evaluation of CD39 as a novel immunoregulatory mechanism invoked by COPD

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

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