Dataset Information

Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-? receptor subunit 1 (IFNGR1).

ABSTRACT: Although IFN-? is required for resolution of Listeria monocytogenes infection, the identities of the IFN-?-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-?R (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-? unresponsiveness in CD8?(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-?-unresponsive CD8?(+) dendritic cells to produce the initial burst of IL-12 induced by IFN-? from TNF-?-activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre(+)Ifngr1(f/f) mice. We also found that Itgax-cre(+)Ifngr1(f/f) mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6C(hi) monocytes. Thus, an IFN-?-driven cascade involving CD8?(+) dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.

SUBMITTER: Lee SH

PROVIDER: S-EPMC3874833 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1).

Lee Sang Hun SH Carrero Javier A JA Uppaluri Ravindra R White J Michael JM Archambault Jessica M JM Lai Koon Siew KS Chan Szeman Ruby SR Sheehan Kathleen C F KC Unanue Emil R ER Schreiber Robert D RD

Journal of immunology (Baltimore, Md. : 1950) 20130918 8

Although IFN-γ is required for resolution of Listeria monocytogenes infection, the identities of the IFN-γ-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-γ unresponsiveness in CD8α(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8α(+) dendritic cells to produce the init ...[more]

PMID: 24048899

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Project description:Protein subunit vaccines present a compelling new area of research for control of tuberculosis (TB). Based on the interaction between Mycobacterium tuberculosis and its host, five stage-specific antigens of M. tuberculosis that participate in TB pathogenesis--Rv1813, Rv2660c, Ag85B, Rv2623, and HspX--were selected. These antigens were verified to be recognized by T cells from a total of 42 whole blood samples obtained from active TB patients, patients with latent TB infections (LTBIs), and healthy control donors. The multistage polyprotein A1D4 was developed using the selected five antigens as a potentially more effective novel subunit vaccine. The immunogenicity and protective efficacy of A1D4 emulsified in the adjuvant MTO [monophosphoryl lipid A (MPL), trehalose-6,6'-dibehenate (TDB), components of MF59] was compared with Bacillus Calmette-Guerin (BCG) in C57BL/6 mice. Our results demonstrated that A1D4/MTO could provide more significant protection against M. tuberculosis infection than the PBS control or MTO adjuvant alone judging from the A1D4-specific Th1-type immune response; however, its efficacy was inferior to BCG as demonstrated by the bacterial load in the lung and spleen, and by the pathological changes in the lung. Antigen-specific single IL-2-secreting cells and different combinations with IL-2-secreting CD4+ T cells were beneficial and correlated with BCG vaccine-induced protection against TB. Antigen-specific IFN-γ+ IL-2+ CD4+ T cells were the only effective biomarker significantly induced by A1D4/MTO. Among all groups, A1D4/MTO immunization also conferred the highest number of antigen-specific single IFN-γ+ and IFN-γ+ TNF-α+ CD4+ T cells, which might be related to the antigen load in vivo, and single IFN-γ+ CD8+ T cells by mimicking the immune patterns of LTBIs or curable TB patients. Our strategy seems promising for the development of a TB vaccine based on multistage antigens, and subunit antigen A1D4 suspended in MTO adjuvant warrants preclinical evaluation in animal models of latent infection and may boost BCG vaccination.

Dataset Information

Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-? receptor subunit 1 (IFNGR1).

Publications

Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1).

Similar Datasets

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