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J Immunol. 2018 May 1;200(9):3244-3258. doi: 10.4049/jimmunol.1701733. Epub 2018 Apr 2.

Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network.

Author information

1
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
2
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
3
Department of Molecular, Cell and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
4
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
5
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115.
6
Division of General Internal Medicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095.
7
Celgene Corporation, Seattle, WA 98102.
8
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523; and.
9
Singapore-MIT Alliance for Research and Technology, Antimicrobial Drug Resistance Interdisciplinary Research Group, Singapore 138602, Singapore.
10
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; rmodlin@mednet.ucla.edu.

Abstract

Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-γ, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.

PMID:
29610140
PMCID:
PMC5916334
[Available on 2019-05-01]
DOI:
10.4049/jimmunol.1701733

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