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.
authors.forename: Roanne
authors.initials: R
authors.lastname: Keeton
authors.forename: Nasiema
authors.initials: N
authors.lastname: Allie
authors.forename: Ivy
authors.initials: I
authors.lastname: Dambuza
authors.forename: Brian
authors.initials: B
authors.lastname: Abel
authors.forename: Nai-Jen
authors.initials: NJ
authors.lastname: Hsu
authors.forename: Boipelo
authors.initials: B
authors.lastname: Sebesho
authors.forename: Philippa
authors.initials: P
authors.lastname: Randall
authors.forename: Patricia
authors.initials: P
authors.lastname: Burger
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fick
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006099:Granuloma / Q000473:pathology; D054884:Host-Pathogen Interactions / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053762:Interleukin-12 Subunit p40; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1