Abstract
BackgroundActivation of innate immunity via pathogen recognition receptors (PRR) modulates adaptive immune responses. PRR ligands are being exploited as vaccine adjuvants and as therapeutics, but their utility in diagnostics has not been explored. Interferon-gamma (IFN-γ) release assays (IGRAs) are functional T cell assays used to diagnose latent tuberculosis infection (LTBI); however, novel approaches are needed to improve their sensitivity.MethodsIn vitro immunomodulation of a whole blood IGRA (QuantiFERON®-TB GOLD In-Tube) with Toll-like receptor agonists poly(I:C), LPS, and imiquimod was performed on blood from subjects with LTBI and negative controls.ResultsIn vitro immunomodulation significantly enhanced the response of T cells stimulated with M. tuberculosis antigens from subjects with LTBI but not from uninfected controls. Immunomodulation of IGRA revealed T cell responses in subjects with LTBI whose T cells otherwise do not respond to in vitro stimulation with antigens alone. Similar to their in vivo functions, addition of poly(I:C) and LPS to whole blood induced secretion of inflammatory cytokines and IFN-α and enhanced the surface expression of antigen presenting and costimulatory molecules on antigen presenting cells.ConclusionsIn vitro immunomodulation of whole blood IGRA may be an effective strategy for enhancing the sensitivity of T cells for diagnosis of LTBI.
Highlights
There are,2 billion individuals worldwide with latent tuberculosis infection (LTBI) [1]
Performed by stimulating patient blood cells in vitro, currently available commercial Interferon-gamma (IFN-c) release assays (IGRAs) measure IFN-c released from antigen-specific T cells upon stimulation with M. tuberculosis antigens that are absent from BCG and most nontuberculous mycobacteria contributing to increased specificity
To test whether immunomodulation of whole blood IGRA with pathogen recognition receptors (PRR) ligands can enhance the response of M. tuberculosis-specific T cells, QFT-GIT assay was performed in 8 individuals with LTBI and 8 uninfected controls in the absence and presence of Toll-like receptor (TLR) agonists poly(I:C), lipopolysaccharide (LPS), and imiquimod
Summary
There are ,2 billion individuals worldwide with latent tuberculosis infection (LTBI) [1]. Because each latent infection carries a 5–10% lifetime risk of progressing to active disease, LTBI comprises a significant reservoir for future TB epidemics [2,3]. Diagnosis of LTBI is made through measuring cell-mediated immune responses to M. tuberculosis antigens and excluding active disease. The interferon-gamma (IFN-c) release assays (IGRAs) were developed for in vitro diagnosis of LTBI [9,10]. Similar to TST, they lack sensitivity for detection of latent (range, 40% to 100%) or active (range, 83% to 90%) infection [9,11]. Interferon-gamma (IFN-c) release assays (IGRAs) are functional T cell assays used to diagnose latent tuberculosis infection (LTBI); novel approaches are needed to improve their sensitivity
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