Novel M tuberculosis Antigen-Specific T-Cells Are Early Markers of Infection and Disease Progression

Abstract

Background Mycobacterium tuberculosis Region-of-Difference-1 gene products present opportunities for specific diagnosis of M. tuberculosis infection, yet immune responses to only two gene-products, Early Secretory Antigenic Target-6 (ESAT-6) and Culture Filtrate Protein-10 (CFP-10), have been comprehensively investigated.MethodsT-cell responses to Rv3873, Rv3878 and Rv3879c were quantified by IFN-γ-enzyme-linked-immunospot (ELISpot) in 846 children with recent household tuberculosis exposure and correlated with kinetics of tuberculin skin test (TST) and ESAT-6/CFP-10-ELISpot conversion over six months and clinical outcome over two years.ResultsResponses to Rv3873, Rv3878, and Rv3879c were present in 20–25% of contacts at enrolment. Rv3873 and Rv3879c responses were associated with and preceded TST conversion (P = 0.02 and P = 0.04 respectively), identifying these antigens as early targets of cell-mediated immunity following M. tuberculosis exposure. Responses to Rv3873 were additionally associated with subsequent ESAT-6/CFP-10-ELISpot conversion (P = 0.04). Responses to Rv3873 and Rv3878 predicted progression to active disease (adjusted incidence rate ratio [95% CI] 3.06 [1.05,8.95; P = 0.04], and 3.32 [1.14,9.71; P = 0.03], respectively). Presence of a BCG-vaccination scar was associated with a 67% (P = 0.03) relative risk reduction for progression to active tuberculosis.ConclusionsThese RD1-derived antigens are early targets of cellular immunity following tuberculosis exposure and T-cells specific for these antigens predict progression to active tuberculosis suggesting diagnostic and prognostic utility.

PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis-Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co-Infection

“…A positive IFN-y response to ESAT-6 and CFP-10 and/or positive response to novel validated MTB-specific peptides including MTB-specific peptides from Rv3873 [ 14 , 15 ] and Rv3615c[ 16 ]. Individuals with HIV co-infection were enrolled if they had risk factors for LTBI and screened for the presence of LTBI [ 17 ].…”

Beyond the IFN-γ horizon: biomarkers for immunodiagnosis of infection withMycobacterium tuberculosis

“…New immunogenic and specific antigens, e.g. associated with M. tuberculosis infection phases, have been described as well as antigens that could render ESAT-6 nonessential in the antigen cocktail [13,[49][50][51][52][53][54][55][56]. Tests based on new antigens are needed if a vaccine based on ESAT-6 proves to be efficacious in humans [48,57,58].…”

The Secreted Protein Rv1860 of Mycobacterium tuberculosis Stimulates Human Polyfunctional CD8+T Cells

“…Polyfunctional T (PFT) cells capable of simultaneously secreting multiple TH1 cytokines were shown to confer protection against TB in the mouse model (18,19); however, studies in humans revealed conflicting results. Several studies showed that human CD4 ϩ PFT cells specific to the secreted antigens ESAT-6, CFP-10, 16-kDa protein, Ag85A, and Ag85B correlated with the bacterial antigen burdens (20)(21)(22)(23); not only did these responses wane with chemotherapy (21,23) but also T cell responses to Rv3873 and Rv3878 from within the RD1 locus in fact predicted progression to active disease (24). These observations led to the suggestion that PFT cells may at best serve as a useful biomarker of active tuberculosis and cure and may have no role in protection.…”