Mycobacterium tuberculosis Protein Rv3841 Activates Dendritic Cells and Contributes to a T Helper 1 Immune Response.

Seunga Choi,Han-Gyu Choi,Ki-Won Shin,Hye-Soo Park,Jae Hwi Lee,Yong Woo Back,Hwa-Jung Kim

doi:10.1155/2018/3525302

Seunga Choi, Han-Gyu Choi + Show 5 more

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https://doi.org/10.1155/2018/3525302

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Abstract

The attenuated vaccine Mycobacterium bovis BCG (Bacille Calmette Guerin) has limited protective efficacy against TB. The development of more effective TB vaccines has focused on the mycobacterial antigens that cause strong T helper 1 (Th1) responses. Mtb protein Rv3841 (bacterioferritin B; BfrB) is known to play a crucial role in the growth of Mtb. Nonetheless, it is unclear whether Rv3841 can induce protective immunity against Mtb. Here, we studied the action of Rv3841 in maturation of dendritic cells (DCs) and its engagement in the development of T-cell immunity. We found that Rv3841 functionally activated DCs by upregulating costimulatory molecules and increased secretion of proinflammatory cytokines. Activation of DCs by Rv3841 was mediated by Toll-like receptor 4 (TLR4), followed by triggering of mitogen-activated protein kinase and nuclear factor-κB signaling pathways. In addition, Rv3841-matured DCs effectively proliferated and polarized Th1 immune response of naïve CD4+ and CD8+ T-cells. Moreover, Rv3841 specifically caused the expansion of CD4+CD44highCD62Llow T-cells from Mtb-infected mice; besides, the T-cells activated by Rv3841-matured DCs inhibited intracellular mycobacterial growth. Our data suggest that Rv3841 induces DC maturation and protective immune responses, a finding that may provide candidate of effective TB vaccines.

Highlights

For tuberculosis (TB) to be removed from the top rank of global health problems within any practical time frame, transformative tools and projects will need to be developed [1]
Priming and expansion of the antigen-specific T-cells after a primary Mycobacterium tuberculosis (Mtb) infection occur in regional lymph nodes that drain the lungs, and these responses are initiated by Mtb-infected dendritic cells (DCs) trafficking from the lungs [3, 4]
Using Bone marrow-derived dendritic cells (BMDCs) differentiation method, bone marrow cells collected from mouse femurs and tibias were incubated for 7 d in RPMI media supplemented with 10% fetal bovine serum (FBS), penicillin/streptomycin (100 unit/mL), nonessential amino acids (0.1 mM), β-mercaptoethanol (50 μM), sodium pyruvate (1 mM), granulocyte macrophage colony-stimulating factor (GM-CSF) (20 ng/mL), and IL-4 (10 ng/mL)

Summary

Introduction

For tuberculosis (TB) to be removed from the top rank of global health problems within any practical time frame, transformative tools and projects will need to be developed [1]. Effective vaccines in latently infected individuals and adults are strongly needed. The immunological mode of action of an effective TB vaccine involves driving the immunodominant CD4+ and CD8+ T-cell responses that can eliminate the invading bacteria. Priming and expansion of the antigen-specific T-cells after a primary Mycobacterium tuberculosis (Mtb) infection occur in regional lymph nodes that drain the lungs, and these responses are initiated by Mtb-infected dendritic cells (DCs) trafficking from the lungs [3, 4]. It has been reported that Mtb modulates the infected DCs to inhibit antigen presentation to T-cells, delaying recruitment of activated T-cells into the lungs from lymph nodes [5]. Effective DC activation and migration are necessary to eliminate Mtb via an adaptive immune response

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