Abstract
In view of the fact that only a small part of the Mtb expressome has been explored for identification of antigens capable of activating human T-cell responses, which is critically required for the design of better TB vaccination strategies, more emphasis should be placed on innovative ways to discover new Mtb antigens and explore their function at the several stages of infection. Better protective antigens for TB-vaccines are urgently needed, also in view of the disappointing results of the MVA85 vaccine, which failed to induce additional protection in BCG-vaccinated infants (1). Moreover, immune responses to relevant antigens may be useful to identify TB-specific biomarker signatures. Here, we describe the potency of novel tools and strategies to reveal such Mtb antigens. Using proteins specific for different Mtb infection phases, many new antigens of the latency-associated Mtb DosR-regulon as well as resuscitation promoting factor proteins, associated with resuscitating TB, were discovered that were recognized by CD4+ and CD8+ T-cells. Furthermore, by employing MHC binding algorithms and bioinformatics combined with high-throughput human T-cell screens and tetramers, HLA-class Ia restricted polyfunctional CD8+ T-cells were identified in TB patients. Comparable methods, led to the identification of HLA-E-restricted Mtb epitopes recognized by CD8+ T-cells. A genome-wide unbiased antigen discovery approach was applied to analyze the in vivo Mtb gene expression profiles in the lungs of mice, resulting in the identification of IVE-TB antigens, which are expressed during infection in the lung, the main target organ of Mtb. IVE-TB antigens induce strong T-cell responses in long-term latently Mtb infected individuals, and represent an interesting new group of TB antigens for vaccination. In summary, new tools have helped expand our view on the Mtb antigenome involved in human cellular immunity and provided new candidates for TB vaccination.
Highlights
T-cell epitopes have been identified in only 7% of all predicted 4000 open reading frames (ORFs) of Mycobacterium tuberculosis (Mtb), and the top 30 most frequently studied protein antigens contain 65% of the known epitopes [4]
In line with the immunogenicity found in mice for Rv0867c, Rv1009, Rv2389c, and Rv2450c [35], we identified the first human Mtb resuscitation promoting factors (Rpfs)-specific T-cell responses against Mtb Rpfs [19], showing www.frontiersin.org
To identify HLA-E-restricted Mtb antigens which could be exploited for TB vaccination, we applied bioinformatics, HLA-E peptide-binding assays, and immunological screening, in analogy to the approach used for identification of classical MHC-Ia restricted CD8 T-cell epitopes [61]
Summary
Almost all TB-vaccine antigen discovery approaches have implicitly relied on the assumption that the Mtb antigens studied are expressed and presented by infected cells, where they are supposedly recognized by T-cells that execute an appropriate effector response. Improved and rational selection is needed to identify candidate antigens with vaccine potential, based on comprehensive knowledge of their patterns of expression, broad immunogenicity, suitability for processing, HLA-binding and induction of protective immunity in relevant model systems.
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