Hydrophobic Mycobacterial Antigens Elicit Polyfunctional T Cells in Mycobacterium bovis Immunized Cattle: Association With Protection Against Challenge?

ABSTRACT Bovine tuberculosis persists as a costly zoonotic disease in numerous countries despite extensive eradication and control efforts. Sequential serum samples obtained from Mycobacterium bovis-infected cattle were evaluated for seroreactivity to mycobacterial antigens. Animals received M. bovis by aerosol, intratonsil, intranasal, or intratracheal inoculation. Assays included the multiantigen print immunoassay for determination of antigen recognition patterns, immunoblot analysis for sensitive kinetic studies, and the VetTB STAT-PAK test, a novel, rapid test based on lateral-flow technology. Responses to MPB83 were detected for all M. bovis-infected animals regardless of the route or strain of M. bovis used for inoculation. Other less commonly recognized antigens included ESAT-6, CFP-10, and MPB70. Responses to MPB83 were detectable as early as 4 weeks after inoculation, were boosted upon injection of purified protein derivatives for skin testing, and persisted throughout the course of each of the four challenge studies. MPB83-specific immunoglobulin M (IgM) was detected prior to MPB83-specific IgG detection; however, early IgM responses rapidly waned, suggesting a benefit of tests that detect both IgM- and IgG-specific antibodies. The VetTB STAT-PAK test detected responses in sera from 60% (15/25) of the animals by 7 weeks after challenge and detected responses in 96% (24/25) of the animals by 18 weeks. These findings demonstrate the potential for new-generation antibody-based tests for the early detection of M. bovis infection in cattle.

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Cross-recognition by T cells of an epitope shared by two unrelated mycobacterial antigens

European Journal of Immunology ◽

10.1002/eji.1830251128 ◽

1995 ◽

Vol 25 (11) ◽

pp. 3173-3179 ◽

Cited By ~ 19

Author(s):

David P. Harris ◽

Hans-Martin Vordermeier ◽

Mahavir Singh ◽

Carlos Moreno ◽

Stipo Jurcevic ◽

...

Keyword(s):

T Cells ◽

Mycobacterial Antigens

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Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Infection and Immunity ◽

10.1128/iai.00943-06 ◽

2006 ◽

Vol 75 (3) ◽

pp. 1154-1166 ◽

Cited By ~ 10

Author(s):

Laura H. Hogan ◽

Dominic O. Co ◽

Jozsef Karman ◽

Erika Heninger ◽

M. Suresh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mycobacterium Bovis ◽

Cd8 T Cells ◽

Bacterial Load ◽

Granulomatous Inflammation ◽

Cd8 T Cell ◽

Activated T Cells ◽

Immunodeficient Mice ◽

Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

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NF-κB Is Involved in Regulation of CD40 Ligand Expression on Mycobacterium bovis Bacillus Calmette-Guérin-Activated Human T Cells

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.3.376-382.2003 ◽

2003 ◽

Vol 10 (3) ◽

pp. 376-382 ◽

Cited By ~ 2

Author(s):

Patricia Méndez-Samperio ◽

Hilda Ayala ◽

Abraham Vázquez

Keyword(s):

T Cells ◽

Mycobacterium Bovis ◽

De Novo ◽

Cd40 Ligand ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Cell Surface Expression ◽

Membrane Expression ◽

Activated T Cells ◽

Cd40l Expression

ABSTRACT Interaction between CD40L (CD154) on activated T cells and its receptor CD40 on antigen-presenting cells has been reported to be important in the resolution of infection by mycobacteria. However, the mechanism(s) by which Mycobacterium bovis bacillus Calmette-Guérin (BCG) up-regulates membrane expression of CD40L molecules is poorly understood. This study was done to investigate the role of the nuclear factor κB (NF-κB) signaling pathway in the regulation of CD40L expression in human CD4+ T cells stimulated with BCG. Specific pharmacologic inhibition of the NF-κB pathway revealed that this signaling cascade was required in the regulation of CD40L expression on the surface of BCG-activated CD4+ T cells. These results were further supported by the fact that treatment of BCG-activated CD4+ T cells with these pharmacological inhibitors significantly down-regulated CD40L mRNA. In this study, inhibitor κBα (IκBα) and IκBβ protein production was not affected by the chemical protease inhibitors and, more importantly, BCG led to the rapid but transient induction of NF-κB activity. Our results also indicated that CD40L expression on BCG-activated CD4+ T cells resulted from transcriptional up-regulation of the CD40L gene by a mechanism which is independent of de novo protein synthesis. Interestingly, BCG-induced activation of NF-κB and the increased CD40L cell surface expression were blocked by the protein kinase C (PKC) inhibitors 1-[5-isoquinolinesulfonyl]-2-methylpiperazine and salicylate, both of which block phosphorylation of IκB. Moreover, rottlerin a Ca2+-independent PKC isoform inhibitor, significantly down-regulated CD40L mRNA in BCG-activated CD4+ T cells. These data strongly suggest that CD40L expression by BCG-activated CD4+ T cells is regulated via the PKC pathway and by NF-κB DNA binding activity.

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Prior Exposure to Live Mycobacterium bovis BCG Decreases Cryptococcus neoformans-Induced Lung Eosinophilia in a Gamma Interferon-Dependent Manner

Infection and Immunity ◽

10.1128/iai.71.6.3384-3391.2003 ◽

2003 ◽

Vol 71 (6) ◽

pp. 3384-3391 ◽

Cited By ~ 19

Author(s):

Gerhard Walzl ◽

Ian R. Humphreys ◽

Ben G. Marshall ◽

Lorna Edwards ◽

Peter J. M. Openshaw ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Mycobacterium Bovis ◽

Mycobacterial Infection ◽

Gamma Interferon ◽

Delayed Type Hypersensitivity ◽

Infection Model ◽

Dependent Manner ◽

Interleukin 5 ◽

Lung Eosinophilia ◽

Mycobacterial Antigens

ABSTRACT Some common childhood infections appear to prevent the development of atopy and asthma. In some Mycobacterium bovis BCG-vaccinated populations, strong delayed-type hypersensitivity responses to mycobacterial antigens are associated with a reduced risk of atopy. Although BCG exposure decreases allergen-induced lung eosinophilia in animal models, little attention has been given to the effect of immunity to BCG on responses against live pathogens. We used the murine Cryptococcus neoformans infection model to investigate whether prior BCG infection can alter such responses. The present study shows that persistent pulmonary BCG infection of C57BL/6 mice induced an increase in gamma interferon, a reduction in interleukin-5, and a decrease in lung eosinophilia during subsequent Cryptococcus infection. This effect was long lasting, depended on the presence of live bacteria, and required persistence of mycobacterial infection in the lung. Reduction of eosinophilia was less prominent after infection with a mutant BCG strain (ΔhspR), which was rapidly cleared from the lungs. These observations have important implications for the development of vaccines designed to prevent Th2-mediated disease and indicate that prior lung BCG vaccination can alter the pattern of subsequent host inflammation.

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Frequencies of IFNγ- and IL-4-producing cells during Mycobacterium bovis BCG infection in two genetically susceptible mouse strains: role of αβ T cells and NK1.1 cells

Immunology Letters ◽

10.1016/0165-2478(95)00009-t ◽

1995 ◽

Vol 46 (1-2) ◽

pp. 15-19 ◽

Cited By ~ 11

Author(s):

Henrique C. Teixeira ◽

Martin E. Munk ◽

Stefan H.E. Kaufmann

Keyword(s):

T Cells ◽

Mycobacterium Bovis ◽

Mouse Strains ◽

Susceptible Mouse ◽

Mycobacterium Bovis Bcg ◽

Αβ T Cells

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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Cancer Immunology Immunotherapy ◽

10.1007/s00262-017-2085-9 ◽

2017 ◽

Vol 67 (2) ◽

pp. 285-298 ◽

Cited By ~ 22

Author(s):

Olivier Gasser ◽

Katrina J. Sharples ◽

Catherine Barrow ◽

Geoffrey M. Williams ◽

Evelyn Bauer ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

High Risk ◽

Phase I ◽

High Risk Melanoma ◽

Risk Melanoma ◽

Melanoma Patients ◽

Polyfunctional T Cells

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Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques

Clinical and Vaccine Immunology ◽

10.1128/cvi.00289-15 ◽

2015 ◽

Vol 22 (9) ◽

pp. 992-1003 ◽

Cited By ~ 26

Author(s):

A. D. White ◽

C. Sarfas ◽

K. West ◽

L. S. Sibley ◽

A. S. Wareham ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Mycobacterium Bovis ◽

Cd8 T Cells ◽

Bcg Vaccine ◽

Effector Memory ◽

Dependent Manner ◽

Aerosol Delivery ◽

Memory Phenotype ◽

Bcg Vaccination

ABSTRACTNine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, theMycobacterium bovisBCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

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