Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent Manner

PLoS Pathogens

Luc Van Kaer¹  Debprasad Chattopadhyay²  Ved Prakash Dwivedi³  Samit Chatterjee³  Yogesh Singh³  Imran Siddiqui³  Pawan Sharma³  Gobardhan Das³ 

[1] Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;ICMR Virus Unit, Calcutta, ID & BG Hospital, GB 4, Beliaghata, Kolkata, India;Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India

关键词: Tuberculosis;    Mycobacterium tuberculosis;    Immune response;    Cell differentiation;    Cytokines;    Vaccines;    T cells;    T helper cells;   

DOI  :  10.1371/journal.ppat.1002378

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY