The recent emergence of Extensively Drug Resistant (XDR) strains of M. tuberculosis, along with HIV-associated TB, has further compounded the problem. M. bovis Bacille Calmette–Guerin (BCG) is still the most widely used vaccine, but exhibits variable efficacy 1. In order to improve upon the current efficacy of BCG vaccination, it is critical to understand the requirements for effective vaccine-induced immune responses following BCG vaccination. The interleukin (IL)-12 type 1 T helper (Th1) pathway
is critical for host immunity against M. tuberculosis in humans 2, and in experimental models 3. Consistent with these findings, BCG vaccine-induced protection against TB is also dependent on the accumulation of Th1-cell memory cells that produce the cytokine IFN-γ that activates CHIR-99021 research buy macrophages for mycobacterial control 4. However, factors required for effective generation of Th1-cell responses following BCG vaccination are not completely understood. The identification of factors required for BCG vaccine-induced
Th1-cell responses will result in a major improvement in our ability to vaccinate effectively against TB and contribute to better control of global TB burdens. The cytokine IL-12, made up of IL-12p35 and IL-12p40 subunits, is critical for the induction of IFN-γ from T and NK T cells 5. IL-23, composed of the p40 and p19 subunit 6, is check details required for maintenance of Th type 17 (Th17) cells 7, 8. Th17 cells produce the cytokines IL-17A (IL-17), IL-17F, IL-21, and IL-22 9 and are involved in the induction of inflammation associated with models of autoimmune diseases 10. In contrast, IL-23-dependent IL-17 responses are important for protective immunity against extracellular bacterial infections via induction of chemokines required for neutrophilic recruitment and bacterial killing 11. However, more recently we and others have shown that IL-17
is also required for protective immunity against some intracellular pathogens such as Francisella tularensis LVS 12 and Chlamydia muriduram 13. IL-17-induced protective immunity against these intracellular pathogens occurs via IL-17-dependent induction of IL-12 in DCs 12, 13 and the resulting generation of Th1-cell responses 12. Accordingly, the absence of the IL-23/IL-17 pathways results in decreased induction of Th1-cell immune responses ID-8 and increased susceptibility to infection 12, 13. Interestingly, pulmonary acute infection with M. bovis BCG also requires IL-17 to drive Th1-cell immune responses, without playing a role in protection 14. These studies project the important question why some intracellular bacteria such as F. tularensis, C. muridarum, and M. bovis BCG 12–14 require IL-17 to induce Th1-cell immunity. In light of these recent findings and since the BCG is the most widely used vaccine worldwide, the goal of this study was to determine if the generation of BCG vaccine-induced Th1-cell immune responses and subsequent protection against M.