Abstract
Background: The analysis of phenotypic characteristics on Mycobacterium tuberculosis (MTB)-specific T cells is a promising approach for the diagnosis of active tuberculosis (aTB) and for monitoring treatment success. We therefore studied phenotypic changes on MTB-specific CD4 T cells upon anti-tuberculosis treatment initiation in relation to the treatment response as determined by sputum culture.Methods: Peripheral blood mononuclear cells from subjects with latent MTB infection (n = 16) and aTB (n = 39) at baseline, weeks 9, 12, and 26 (end of treatment) were analyzed after intracellular interferon gamma staining and overnight stimulation with tuberculin. Liquid sputum cultures were performed weekly until week 12 and during 4 visits until week 26.Results: T cell activation marker expression on MTB-specific CD4 T cells differed significantly between subjects with aTB and latent MTB infection with no overlap for the frequencies of CD38pos and Ki67pos cells (both p < 0.0001). At 9 weeks after anti-TB treatment initiation the frequencies of activation marker (CD38, HLA-DR, Ki67) positive MTB-specific, but not total CD4 T cells, were significantly reduced (p < 0.0001). Treatment induced phenotypic changes from baseline until week 9 and until week 12 differed substantially between individual aTB patients and correlated with an individual's time to stable sputum culture conversion for expression of CD38 and HLA-DR (both p < 0.05). In contrast, the frequencies of maturation marker CD27 positive MTB-specific CD4 T cells remained largely unchanged until week 26 and significantly differed between subjects with treated TB disease and latent MTB infection (p = 0.0003).Discussion: Phenotypic changes of MTB-specific T cells are potential surrogate markers for tuberculosis treatment efficacy and can help to discriminate between aTB (profile: CD38pos, CD27low), treated TB (CD38neg, CD27low), and latent MTB infection (CD38neg, CD27high).
Highlights
Novel diagnostic tools for improved detection of active tuberculosis and for monitoring TB treatment are urgently required to succeed in the WHO END TB strategy, which— in the abscence of an efficacious Mycobacterium tuberculosis (MTB) vaccine - sets the ambitious target of a world free of tuberculosis by 2030 [1]
We addressed whether changes in the frequencies of T cell activation marker positive MTB-specific CD4 T cells between baseline and W9; and between baseline and W12 were linked to treatment-induced bacterial clearance using the primary PanACEA study endpoint—time to stable culture negativity. 32 of 39 subjects had TAM-TB results at baseline and at W12 and/or W9 and the slope for the change in expression of the individual TAMs after treatment initiation could be determined. 15 of these 32 subjects had an accurate endpoint determination of ≤ 4 weeks between the last positive and stable culture conversion (Figure 7)
Substantial reductions in the expression of activation markers on MTB-specific CD4 T cells were observed at W9 into TB treatment for most patients
Summary
Novel diagnostic tools for improved detection of active tuberculosis (aTB) and for monitoring TB treatment are urgently required to succeed in the WHO END TB strategy, which— in the abscence of an efficacious MTB vaccine - sets the ambitious target of a world free of tuberculosis by 2030 [1]. Recent studies have highlighted the diagnostic potential of a flow cytometry based approach to detect and differentiate aTB disease from latent Mycobacterium tuberculosis (MTB) infection (LTBI) via phenotypic and/or functional characterization of MTB-specific T cells in adults and children [2,3,4,5,6,7,8,9,10,11,12]. We studied phenotypic changes on MTB-specific CD4 T cells upon anti-tuberculosis treatment initiation in relation to the treatment response as determined by sputum culture
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