ABSTRACTTheMycobacterium bovisBCG vaccine is the only tuberculosis (TB) vaccine available, yet it provides limited protection against pulmonary TB in adults and fails to protect against TB reactivation. We hypothesized that immunity againstMycobacterium tuberculosis“resuscitation-promoting factors” (Rpfs), which are small bacterial proteins that promote proliferation of dormant mycobacteria, may be relevant in the human immune response toM. tuberculosis. In previous unpublished work, we found that Rpfs Rv0867c and Rv2389c induced gamma interferon (IFN-γ) production in the blood of TB patients' healthy household contacts in several different African populations. Here we examine these two dominant Rpf antigens in more detail and define the nature of the responding T-cell subsets. Multiparameter cytokine profiling showed that Rv2389c and, to a lesser extent, Rv0867c were recognized by mycobacterium-responsive healthy Dutch individuals; peptide-scanning revealed several epitopes, including a single immunodominant epitope in Rv2389c. Rv0867c and, to a lesser extent, Rv2389c Rpf-specific T-cell responses were maintained for decades in long-termM. tuberculosisnonprogressors. Prominent Rv0867c-specific double- and single-cytokine-producing CD8+T-cell subset responses were found, including a large population of CD8+effector memory and effector T-cell subsets. We conclude thatM. tuberculosisRpf antigens are important targets in the human immune response toM. tuberculosisand represent interesting TB vaccine candidate antigens.
Modelling the human immune response mechanisms to mycobacterium tuberculosis infection in the lungs
