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

26 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

Fingerprint

Mycobacterium tuberculosis
Interleukin-12 Subunit p40
Immunity
Mycobacterium Infections
Lung
Granuloma
Cytokines
T-Lymphocytes

Cite this

Keeton, R., Allie, N., Dambuza, I., Abel, B., Hsu, N-J., Sebesho, 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

Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis. / Keeton, Roanne; Allie, Nasiema; Dambuza, Ivy; Abel, Brian; Hsu, Nai-Jen; Sebesho, Boipelo; Randall, Philippa; Burger, Patricia; Fick, Elizabeth; Quesniaux, Valerie F. J.; Ryffel, Bernhard; Jacobs, Muazzam (Corresponding Author).

In: The Journal of Clinical Investigation, Vol. 124, No. 4, 04.2014, p. 1537-1551.

Research output: Contribution to journalArticle

Keeton, R, Allie, N, Dambuza, I, Abel, B, Hsu, N-J, Sebesho, B, Randall, P, Burger, P, Fick, E, Quesniaux, VFJ, Ryffel, B & Jacobs, M 2014, 'Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis', The Journal of Clinical Investigation, vol. 124, no. 4, pp. 1537-1551. https://doi.org/10.1172/JCI45005
Keeton, Roanne ; Allie, Nasiema ; Dambuza, Ivy ; Abel, Brian ; Hsu, Nai-Jen ; Sebesho, Boipelo ; Randall, Philippa ; Burger, Patricia ; Fick, Elizabeth ; Quesniaux, Valerie F. J. ; Ryffel, Bernhard ; Jacobs, Muazzam. / Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis. In: The Journal of Clinical Investigation. 2014 ; Vol. 124, No. 4. pp. 1537-1551.
@article{fd3640c5b2d3480c8c080353dacdbde1,
title = "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.",
author = "Roanne Keeton and Nasiema Allie and Ivy Dambuza and Brian Abel and Nai-Jen Hsu and Boipelo Sebesho and Philippa Randall and Patricia Burger and Elizabeth Fick and Quesniaux, {Valerie F. J.} and Bernhard Ryffel and Muazzam Jacobs",
note = "This study was supported by the National Research Foundation (South Africa), the Medical Research Council (South Africa), University of Cape Town, National Health and Laboratory Services (South Africa), and the European Union (FP6 NEST project no. 028190 “TB REACT”). Research was carried out within the scope of the Franco/South African Laboratory “TB Immunity” (Associated International Laboratory [AIL] no. 236). The authors thank Marylin Tyler for contributing to the histopathology, Natalie Neuwenhuizen for constructive critique of the manuscript, and the staff of the Division of Immunology and the Animal Unit at UCT for contributing to animal care and technical support.",
year = "2014",
month = "4",
doi = "10.1172/JCI45005",
language = "English",
volume = "124",
pages = "1537--1551",
journal = "The Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

TY - JOUR

T1 - Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis

AU - Keeton, Roanne

AU - Allie, Nasiema

AU - Dambuza, Ivy

AU - Abel, Brian

AU - Hsu, Nai-Jen

AU - Sebesho, Boipelo

AU - Randall, Philippa

AU - Burger, Patricia

AU - Fick, Elizabeth

AU - Quesniaux, Valerie F. J.

AU - Ryffel, Bernhard

AU - Jacobs, Muazzam

N1 - This study was supported by the National Research Foundation (South Africa), the Medical Research Council (South Africa), University of Cape Town, National Health and Laboratory Services (South Africa), and the European Union (FP6 NEST project no. 028190 “TB REACT”). Research was carried out within the scope of the Franco/South African Laboratory “TB Immunity” (Associated International Laboratory [AIL] no. 236). The authors thank Marylin Tyler for contributing to the histopathology, Natalie Neuwenhuizen for constructive critique of the manuscript, and the staff of the Division of Immunology and the Animal Unit at UCT for contributing to animal care and technical support.

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

U2 - 10.1172/JCI45005

DO - 10.1172/JCI45005

M3 - Article

C2 - 24569452

VL - 124

SP - 1537

EP - 1551

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -