Browsing by Author "Lundtoft Christian"

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    Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis
    (PLOS, 2017) Lundtoft Christian; Nausch Norman; Owusu-Dabo Ellis; Jacobsen Marc; Lang Franziska....et al
    T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoim munity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We per formed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/ sIL-7R and mIL-7R expression, respectively. IL-7-dependent T-cell functions were deter mined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by ana lysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normal ised during therapy and recovery. Furthermore, tuberculosis patients had lower levels ofmIL-7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indi cated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted cyto kine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T-cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients.
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    Two-Hit in vitro T-Cell Stimulation Detects Mycobacterium tuberculosis Infection in QuantiFERON Negative Tuberculosis Patients and Healthy Contacts From Ghana
    (Frontiers In Immunology, 2019) Adankwah Ernest; Lundtoft Christian; Owusu-Dabo Ellis; Franken L. M. C. Kees...et al
    IFN-γ release assays [e.g., QuantiFERON (QFT)] are widely used for diagnosis of Mycobacterium tuberculosis (Mtb) infection. T-cell responses against QFT antigens ESAT6 and CFP10 are highly Mtb specific but previous studies indicated suboptimal assay sensitivity. Especially for potentially infected healthy contacts (HCs) of tuberculosis patients, alternative antigen usage and more sensitive tests may contribute to improved detection of latent Mtb infection. In a pilot case-control study of tuberculosis patients (n = 22) and HCs (n = 20) from Ghana, we performed multifaceted in vitro assays to identify optimal assay conditions. This included a two-hit stimulation assay, which is based on initial and second re-stimulation with the same antigen on d6 and intracellular IFN-γ analysis, to compare T-cell responses against ESAT6/CFP10 (E6/C10) and selected latency antigens (i.e. Rv2628, Rv1733, Rv2031, Rv3407) of Mtb. Considerable subgroups of tuberculosis patients (64%) and HCs (75%) had negative or indeterminate QFT results partially accompanied by moderate PHA induced responses and high IFN-γ background values. Intracellular IFN-γ analysis of E6/C10 specific CD4+ T-cell subpopulations and evaluation of responder frequencies had only moderate effects on assay sensitivity. However, two-hit in vitro stimulation significantly enhanced E6/C10 specific IFN-γ positive T-cell proportions especially in QFT non-responders, and in both study groups. Mtb latency antigen-specific T cells against Rv1733 and Rv2628 were especially detected in HCs after two-hit stimulation and T-cell responses against Rv2628 were highly capable to discriminate tuberculosis patients and HCs. Two-hit in vitro stimulation may improve moderate sensitivity of short term IFN-γ based assays, like QFT, to detect Mtb infection. Latency stage-specific antigens added significantly to detection of Mtb infection in HCs and tuberculosis patients with negative QFT test results