Figure 1. The three stages of tuberculosis.

Stage 1: Infection of Mycobacterium tuberculosis (Mtb) frequently occurs at a young age. Metabolically active Mtb are inhaled and subsequently T-cells are stimulated which carry the major burden of acquired immunity. These include major histocompatability complex class II (MHC II)-restricted CD4 T-cells and MHC I-restricted CD8 T-cells. B cells are also activated but their protective role in TB remains elusive. Pre-exposure vaccines are given at this early stage. Novel pre-exposure vaccine candidates are given very soon after birth and thus generally before infection with Mtb. They either substitute for Bacille Calmette Guérin (BCG) or boost immunity induced by BCG. Stage 2: Acquired immunity comprising CD4 and CD8 T-cells contains Mtb in a dormant stage within solid granulomas. T-cells produce type I cytokines and cytolytic effector molecules. They become memory T-cells which concomitantly produce multiple cytokines. Individuals remain latently infected without clinical signs of active tuberculosis (TB). Post-exposure vaccines are given to adolescents or adults who are latently infected but healthy. Stage 3: Mechanisms leading to deficient immunity and disease reactivation are numerous and include production of suppressive cytokines such as interleukin (IL)-10 and transforming growth factor-beta (TGFβ) by T helper 2 (Th2) cells and regulatory T(reg) cells as well as T-cell exhaustion mediated by inhibitory receptor-coreceptor interactions on antigen presenting cells (APCs) and T-cells. Mtb becomes metabolically active and granulomas become caseous. Mtb can be spread to other organs and to other individuals. Therapeutic vaccines are given to TB patients in adjunct to chemotherapy.