Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection

Mpande, Cheleka A M; Musvosvi, Munyaradzi; Rozot, Virginie; Mosito, Boitumelo; Reid, Timothy D.; Schreuder, Constance; Lloyd, Tessa; Bilek, Nicole; Huang, Huang; Obermoser, Gerlinde; Davis, Mark M.; Rühwald, Morten; Hatherill, Mark; Scriba, Thomas J.; Nemes, Elisa; Team, Acs Study

doi:10.1164/rccm.202007-2686oc

Cited by 29 publications

(31 citation statements)

References 30 publications

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“…This study focused on understanding T cell immunobiology during acquisition of M.tb infection and the discovery of potential biomarkers to distinguish between recent and remote M.tb infection. Development of a simplified assay to identify such individuals in clinical settings, including validation in a test cohort and performance as a marker of disease progression, are beyond the scope of this paper and were reported separately [43]. In this follow-up study [43], we showed that levels of HLA-DR expression on CFP-10/ESAT-6-specific T cells were not significantly different in TB patients compared to recently infected individuals.…”

Section: Discussionmentioning

confidence: 80%

“…Development of a simplified assay to identify such individuals in clinical settings, including validation in a test cohort and performance as a marker of disease progression, are beyond the scope of this paper and were reported separately [43]. In this follow-up study [43], we showed that levels of HLA-DR expression on CFP-10/ESAT-6-specific T cells were not significantly different in TB patients compared to recently infected individuals. This observation further supports the hypothesis that T cell activation may track levels of in vivo antigen exposure, which is expected to be higher during recent M.tb infection and active disease compared to remote asymptomatic infection.…”

Section: Discussionmentioning

confidence: 80%

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Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

et al. 2021

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Background Recent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection. Methods Healthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterised M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+. Findings CFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection. Interpretation Recent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection. Funding US National Institutes of Health (NIH), Bill and Melinda Gates Foundation, South African National Research Foundation, South African Medical Research Council, and Aeras.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 80%

Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

et al. 2021

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“…Last, HLA-DR expression on M. tuberculosis –specific CD4 + T cells has been shown to be a robust marker to distinguish active or subclinical TB from latent M. tuberculosis infection, regardless of HIV infection ( 46 , 47 ). Thus, to define whether COVID-19 can promote M. tuberculosis reactivation, we compared the expression of HLA-DR on M. tuberculosis –specific CD4 + T cells in the different cohorts ( Figure 7D ).…”

Section: Resultsmentioning

confidence: 99%

Relationship of SARS-CoV-2–specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection

Riou¹,

Bruyn²,

Stek³

et al. 2021

Journal of Clinical Investigation

132

105

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T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2–specific (SARS-CoV-2–specific) CD4 + T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non–COVID-19 patients. We showed that SARS-CoV-2–specific CD4 + T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1–mediated CD4 + T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2–specific CD4 + T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis –specific CD4 + T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2–specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

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“…It is not possible to state if TB therapy induced a protective cytokine profile in TBI-IMID; however, these patients have been followed for 6 years and none of them developed until now active-TB disease. Since the phenotype studied based on CD45RA and CD27 did not allow to define a particular profile over time, we may need to better characterize the response using also other activation markers such as HLA-DR ( 29 , 60 ).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Immune Response in Patients With Immune-Mediated Inflammatory Disease

et al. 2021

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Subjects with immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis (RA), have an intrinsic higher probability to develop active-tuberculosis (TB) compared to the general population. The risk ranges from 2.0 to 8.9 in RA patients not receiving therapies. According to the WHO, the RA prevalence varies between 0.3% and 1% and is more common in women and in developed countries. Therefore, the identification and treatment of TB infection (TBI) in this fragile population is important to propose the TB preventive therapy. We aimed to study the M. tuberculosis (Mtb) specific T-cell response to find immune biomarkers of Mtb burden or Mtb clearance in patients with different TB status and different risk to develop active-TB disease. We enrolled TBI subjects as example of Mtb-containment, the active-TB as example of a replicating Mtb status, and the TBI-IMID as fragile population. To study the Mtb-specific response in a condition of possible Mtb sterilization, we longitudinally enrolled TBI subjects and active-TB patients before and after TB therapy. Peripheral blood mononuclear cells were stimulated overnight with Mtb peptides contained in TB1- and TB2-tubes of the Quantiferon-Plus kit. Then, we characterized by cytometry the Mtb-specific CD4 and CD8 T cells. In TBI-IMID, the TB therapy did not affect the ability of CD4 T cells to produce interferon-γ, tumor necrosis factor-α, and interleukin-2, their functional status, and their phenotype. The TB therapy determined a contraction of the triple functional CD4 T cells of the TBI subjects and active-TB patients. The CD45RA- CD27+ T cells stood out as a main subset of the Mtb-specific response in all groups. Before the TB-preventive therapy, the TBI subjects had higher proportion of Mtb-specific CD45RA-CD27+CD4+ T cells and the active-TB subjects had higher proportion of Mtb-specific CD45RA-CD27-CD4+ T cells compared to other groups. The TBI-IMID patients showed a phenotype similar to TBI, suggesting that the type of IMID and the IMID therapy did not affect the activation status of Mtb-specific CD4 T cells. Future studies on a larger and better-stratified TBI-IMID population will help to understand the change of the Mtb-specific immune response over time and to identify possible immune biomarkers of Mtb-containment or active replication.

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Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection

Cited by 29 publications

References 30 publications

Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

Relationship of SARS-CoV-2–specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection

Mycobacterium tuberculosis Immune Response in Patients With Immune-Mediated Inflammatory Disease

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