Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis
Roanne Keeton, … , Bernhard Ryffel, Muazzam Jacobs
Roanne Keeton, … , Bernhard Ryffel, Muazzam Jacobs
Published April 1, 2014; First published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1537-1551. https://doi.org/10.1172/JCI45005.
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Research Article Microbiology

Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis

Abstract

Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. TNFRp75–/– mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40–dependent migration of DCs to lung draining LNs of infected TNFRp75–/– mice was substantially higher than that observed in WT M. tuberculosis–infected animals and was associated with enhanced frequencies of activated M. tuberculosis–specific IFN-γ–expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 in M. tuberculosis–infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by TNFRp75–/– BMDCs. Addition of exogenous TNFRp75 to TNFRp75–/– BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome.

Authors

Roanne Keeton, Nasiema Allie, Ivy Dambuza, Brian Abel, Nai-Jen Hsu, Boipelo Sebesho, Philippa Randall, Patricia Burger, Elizabeth Fick, Valerie F.J. Quesniaux, Bernhard Ryffel, Muazzam Jacobs

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Figure 2

Reduced pulmonary pathology and inflammation in M. tuberculosis–infected TNFRp75–/– mice.

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Reduced pulmonary pathology and inflammation in M. tuberculosis–infected...
WT, TNFRp75–/–, TNFRp55–/–, and TNFRp55/75–/– mice were infected by aerosol inhalation with 50–100 CFU M. tuberculosis. Mice were sacrificed at the indicated time points, pulmonary pathology was recorded 35 days after infection (A), lung weights were assessed (B), and total pulmonary cell numbers at day 35 after infection were determined (C). Values are mean ± SEM of 4 mice per group. (D–K) Lungs were removed on days 28 (D–G) and 35 (H–K), fixed in formalin, embedded in wax, and sectioned, after which H&E staining was performed. Arrows denote the presence of granuloma structures; × symbols denote tissue necrosis. Original magnification, ×40. Data represent 1 of 3 similar experiments. *P < 0.05, **P < 0.01, ANOVA.