Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner

• Published in: PLoS pathogens 2011-11, Vol.7 (11), p.e1002378-e1002378
• Main Authors: Chatterjee, Samit, Dwivedi, Ved Prakash, Singh, Yogesh, Siddiqui, Imran, Sharma, Pawan, Van Kaer, Luc, Chattopadhyay, Debprasad, Das, Gobardhan
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; BCG Vaccine - immunology; Biology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Health aspects; Immune response; Immune system; Immunology; Infections; Interleukin-6 - biosynthesis; Lung - immunology; Lung - microbiology; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium bovis - immunology; Mycobacterium bovis - pathogenicity; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - pathogenicity; Myeloid Differentiation Factor 88 - metabolism; Physiological aspects; Proteins; T cell receptors; T cells; Th1 Cells - immunology; Th17 Cells - immunology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Transforming Growth Factor beta - biosynthesis; Tuberculosis; Tuberculosis - immunology; Tuberculosis - prevention & control; Vaccines
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002378

Despite its relatively poor efficacy, Bacillus Calmette-Guérin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-β production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re-challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvΔRD1). However, TLR-2 knockout (TLR-2⁻/⁻) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvΔRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy.