title: Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis.
abstract: Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in M. tuberculosis infection was examined. All Socs3(fl/fl) LysM cre, Socs3(fl/fl) lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130(F/F) mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3(fl/fl) lck cre mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. Socs3(fl/fl) lck cre γδ+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Carow
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Reuschl
authors.forename: Dolores
authors.initials: D
authors.lastname: Gavier-Widén
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Chambers
authors.forename: Martin E
authors.initials: ME
authors.lastname: Rottenberg
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007111:Immunity, Cellular; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D050796:STAT3 Transcription Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control
chemical_list: D001500:BCG Vaccine; D016207:Cytokines; C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130