Abstract
Background. Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection.Methods. A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Polychromatic flow cytometry was used to measure CD4+ and CD8+ T-cell subset phenotype and secretion of interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α).Results. Frequencies of CD4+ and CD8+ cells secreting IFN-γ-only, TNF-α-only and dual IFN-γ/TNF-α were greater in active tuberculosis vs latent tuberculosis infection. All M. tuberculosis-specific CD4+ subsets, with the exception of IL-2-only cells, switched from central to effector memory phenotype in active tuberculosis vs latent tuberculosis infection, accompanied by a reduction in IL-7 receptor α (CD127) expression. The frequency of PPD-specific CD4+ TNF-α-only-secreting T cells with an effector phenotype accurately distinguished active tuberculosis from latent tuberculosis infection with an area under the curve of 0.99, substantially more discriminatory than measurement of function alone.Conclusions. Combined measurement of T-cell phenotype and function defines a highly discriminatory biomarker of tuberculosis disease activity. Unlocking the diagnostic and monitoring potential of this combined approach now requires validation in large-scale prospective studies.
Highlights
Changes in the phenotype and function of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4+ and CD8+ T-cell subsets in response to stage of infection may allow discrimination between active tuberculosis and latent tuberculosis infection
Frequencies of CD4+ and CD8+ cells secreting interferon γ (IFN-γ)-only, tumor necrosis factor (TNF)-α-only and dual IFN-γ/tumor necrosis factor α (TNF-α) were greater in active tuberculosis vs latent tuberculosis infection
Pollock et al Functional CD4+ and CD8+ T-cell subsets have been defined based on single-cell cytokine signatures
Summary
A prospective comparison of M. tuberculosis-specific cellular immunity in subjects with active tuberculosis and latent tuberculosis infection, with and without human immunodeficiency virus (HIV) coinfection. Participants were ≥18 years, provided written, informed consent, and were eligible if under clinical investigation for active tuberculosis, undergoing latent tuberculosis infection screening, or had recognized tuberculosis risk factors (eg, known tuberculosis contact). Suspected active tuberculosis was confirmed microbiologically by the clinical diagnostic laboratory. Latent tuberculosis infection was defined as a positive response to RD-1 antigens in either T-SPOT.TB (carried out in routine clinical work up) or M. tuberculosis IFN-γ ELISpot (carried out for the current study) in the absence of symptomatic, microbiological, or radiological evidence of active tuberculosis. Presence of HIV infection was confirmed by third or fourth generation sero-assay performed by the clinical diagnostic laboratory and using HIV-1 type specific enzyme immunoassay (EIA), according to national standards. HIV diagnostics were available for all patients with active tuberculosis (in line with the national screening policy) and the majority of those with latent tuberculosis infection; the remainder had no risk factors for HIV and normal CD4: CD8 lymphocyte ratios and were classified as HIV-uninfected
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