Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis

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 (Corresponding Author)

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1537-1551
Number of pages15
JournalThe Journal of Clinical Investigation
Volume124
Issue number4
Early online date24 Feb 2014
DOIs
Publication statusPublished - Apr 2014

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    Keeton, R., Allie, N., Dambuza, I., Abel, B., Hsu, N-J., Sebesho, B., Randall, P., Burger, P., Fick, E., Quesniaux, V. F. J., Ryffel, B., & Jacobs, M. (2014). Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis. The Journal of Clinical Investigation, 124(4), 1537-1551. https://doi.org/10.1172/JCI45005