Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain

// Woo Sik Kim 1,* , Jong-Seok Kim 1,* , Seung Bin Cha 1 , Hongmin Kim 1 , Kee Woong Kwon 1 , So Jeong Kim 1 , Seung Jung Han 1 , Soo Young Choi 1 , Sang-Nae Cho 1 , Jong-Hwan Park 2 and Sung Jae Shin 1 1 Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea 2 Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea * These authors have contributed equally to this work Correspondence to: Jong-Hwan Park, email: // Sung Jae Shin, email: // Keywords : tuberculosis; DC maturation; Toll-like receptor 2; multifunctional T cell; subunit vaccine; Immunology and Microbiology Section; Immune response; Immunity Received : December 07, 2015 Accepted : April 06, 2016 Published : April 16, 2016 Abstract Identification of vaccine target antigens (Ags) that induce Ag-specific Th1 immunity is the first step toward the development of a tuberculosis vaccine. Here, we evaluated the Mycobacterium tuberculosis (Mtb) protein Rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (DCs). Rv3628 activated DCs, increasing their expression of cell surface molecules and augmenting their production of TNF-α, IL-1β, IL-6, and IL-12p70. Rv3628 mediated these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. Rv3628-stimulated DCs induced the expansion of OVA-specific CD4 + and CD8 + T cells, which secreted IFN-γ and IL-2. Rv3628-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 Ag in samples of lung and spleen cells collected from Mtb-infected mice. Finally, an Rv3628 subunit vaccine adjuvanted with dimethyldioctadecylammonium liposomes containing monophosphoryl lipid-A caused significant reductions in bacterial counts and lung inflammation after challenge with the hyper-virulent Mtb K strain. Importantly, protective efficacy was correlated with the generation of Rv3628-specific CD4 + T cells co-producing IFN-γ, TNF-α and IL-2 and exhibiting an elevated IFN-γ recall response. Thus, Rv3628 polarizes DCs toward a Th1 phenotype and promotes protective immunity against Mtb infection.