title: Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation.
abstract: The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NSmice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NSmice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection.
authors.affiliation: Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
authors.forename: Ivy M
authors.initials: IM
authors.lastname: Dambuza
authors.affiliation: Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
authors.forename: Roanne
authors.initials: R
authors.lastname: Keeton
authors.affiliation: Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
authors.forename: Nai-Jen
authors.initials: NJ
authors.lastname: Hsu
authors.affiliation: Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
authors.forename: Nasiema
authors.initials: N
authors.lastname: Allie
authors.affiliation: CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, 45071 Orleans, France.
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.affiliation: CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, 45071 Orleans, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.|National Health Laboratory Service, South Africa.|South African Medical Research Council, Cape Town, South Africa.
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018960:Hyaluronan Receptors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D055985:Latent Tuberculosis / Q000276:immunology*; D008168:Lung / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D009569:Nitric Oxide / Q000737:chemistry; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: C476399:Cd44 protein, mouse; D016207:Cytokines; D018960:Hyaluronan Receptors; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D009569:Nitric Oxide; D007371:Interferon-gamma