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

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.

The outer membrane protein Tp92 of Treponema pallidum induces human mononuclear cell death and IL‐8 secretion

“…CD14 exerts its effect on cell surfaces together with TLRs, which can also recognize PAMPs. CD14 can recognize LPS together with MD2/TLR4 and can recognize PGN, LTA or lipoprotein together with TLR2 . In addition, CD14 is a common receptor of TLR7 and TLR9 .…”

“…CD14 can recognize LPS together with MD2/TLR4 23 and can recognize PGN, LTA or lipoprotein together with TLR2. [24][25][26][27][28] In addition, CD14 is a common receptor of TLR7 and TLR9. 29 When the LPS concentration is low, CD14 helps TLR4 leading to cell death.…”

Vaccine efficacy of a Mycobacterium tuberculosis Beijing‐specific proline‐glutamic acid (PE) antigen against highly virulent outbreak isolates

“…We next investigated the molecular role of MTBK_20640 in DC activation in more detail. Several cell wall‐associated PE and PPE family Ags induce immune responses by interacting with TLRs (9, 16, 18). We asked whether MTBK_20640 was recognized by and interacted with DC TLRs.…”

“…In addition, TLR2 interacts with cell wall–associated Mtb Ags, such as lipoproteins (14, 15) and proline‐glutamic acid (PE) or PPE proteins (16, 17). TLR2‐mediated interaction of APCs with Mtb Ags can induce the activation of NF‐κB and MAPK pathways, leading to enhanced expression of surface molecules and production of immunoregulatory cytokines, which leads to enhanced T h 1‐polarized responses and effector functions against Mtb (13, 18, 19).…”

Tuberculosis vaccines — perspectives from the NIH/NIAID Mycobacteria vaccine testing program

“…Whether these cells are sufficient to induce protective immunity is not fully understood, leaving the critical role of a T cell during M. tuberculosis infection, cytokine production, cytolytic activity and antibody engagement to be determined. Given the diverse type and functions of dendritic cells (DC) the need to combine an adjuvant with an appropriate route of administration is important in directing subsequent adaptive immunity [47, 67, 68]. For example during mucosal vaccine delivery, defining the role of TLRs in DC activation is important [60], though other pulmonary cells including epithelial cells and macrophages may also be involved and contribute to a network of interactions that lead to productive adaptive immunity [69].…”