Initiation of Acquired Immunity in the Lungs of Mice Lacking Lymph Nodes after Infection with Aerosolized Mycobacterium tuberculosis

Kashino, Suely S.; Vallerskog, Therese; Martens, Gregory W.; Troudt, JoLynn; Keyser, Andrew; Taylor, Jennifer; Izzo, Angelo A.; Kornfeld, Hardy; Campos-Neto, Antônio

doi:10.2353/ajpath.2010.090446

Cited by 17 publications

(24 citation statements)

References 24 publications

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“…Studies using fluorescent M. bovis BCG or fluorescent Mtb H37Rv (8,16), or using adoptive transfer of fluorescently-labeled DC and macrophages pulsed in vitro with irradiated Mtb H37Rv (17), established that DC preferentially carry bacilli to the LN. Work from several groups confirms that immunity to Mtb after aerosol challenge is primed in the lung-draining LN (7,17–19), although priming can occur at other sites in mice lacking LN (20) or lacking CCR7 (21). Our data presented here suggest that DM exacerbates the already slow pace of generating immunity to Mtb.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis

Vallerskog

Martens

Kornfeld

2010

The Journal of Immunology

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157

154

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Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB) but the defect in protective immunity responsible for this has not been defined. We previously reported that streptozotocin-induced DM impaired TB defense in mice, resulting in higher pulmonary bacterial burden, more extensive inflammation, and higher expression of several proinflammatory cytokines known to play a protective role in TB. In the current study, we tested the hypothesis that DM leads to delayed priming of adaptive immunity in the lung-draining lymph nodes (LNs) following low dose aerosol challenge with virulent Mycobacterium tuberculosis. We show that M. tuberculosis-specific IFN-γ–producing T cells arise later in the LNs of diabetic mice than controls, with a proportionate delay in recruitment of these cells to the lung and stimulation of IFN-γ–dependent responses. Dissemination of M. tuberculosis from lung to LNs was also delayed in diabetic mice, although they showed no defect in dendritic cell trafficking from lung to LNs after LPS stimulation. Lung leukocyte aggregates at the initial sites of M. tuberculosis infection developed later in diabetic than in nondiabetic mice, possibly related to reduced levels of leukocyte chemoattractant factors including CCL2 and CCL5 at early time points postinfection. We conclude that TB increased susceptibility in DM results from a delayed innate immune response to the presence of M. tuberculosis-infected alveolar macrophages. This in turn causes late delivery of Ag-bearing APC to the lung draining LNs and delayed priming of the adaptive immune response that is necessary to restrict M. tuberculosis replication.

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Section: Discussionmentioning

confidence: 99%

Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis

Vallerskog

Martens

Kornfeld

2010

The Journal of Immunology

Self Cite

157

154

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“…The requirement of the LN in priming T-cell responses during pulmonary infection has long been a point of debate amongst immunologists. Recently, two papers by Day et al and Kashino et al indicate that LNs are dispensable for T-cell priming [45,46]. In these studies, areas of inducible bronchus-associated lymphoid tissues (iBALT) developed prior to day 14 postinfection and persisted throughout the course of infection.…”

Section: Migration Of Dcs To the Ln And T-cell Primingmentioning

confidence: 97%

Pulmonary mucosal dendritic cells in T-cell activation: implications for TB therapy

McCormick

Shaler

Xing

2011

Expert Review of Respiratory Medicine

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Mycobacterium tuberculosis, the causative agent of pulmonary TB, causes chronic intracellular infection of lung-resident antigen-presenting cells, including macrophages and dendritic cells (DCs). Life-long bacterial control requires robust T-cell immune responses. Lung DCs are critical for initiating and co-ordinating adaptive immune responses against TB. The recent description of previously uncharacterized DC subsets has prompted the re-examination of lung DCs and their role in priming antimycobacterial T-cell responses. While there is some data on these new DCs in their naive state, very little is known about how these DCs respond to pulmonary mycobacterial infection. In this article, we attempt to identify the major antigen-presenting cell subsets that may be critical to lymph node homing, T-cell priming and controlling mycobacterial infection. We further examine the areas of DC heterogeneity that may relate to differential susceptibility between mouse strains. Furthermore, we discuss how DCs may be manipulated and exploited as a cell-based prophylactic TB vaccine and the prospect of using this strategy for post-M. tuberculosis exposure settings.

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“…Sections were washed and incubated with biotinylated secondary antibody at 1:2000 for 2 hours at room temperature, followed by washing and incubation with avidin-biotin complex (Vectastain Elite ABC kit; Vector Laboratories, Burlingame, CA, USA) at 1:100 for 1 hour at room temperature. Sections were counterstained with Mayer hematoxylin for 2 to 5 minutes and mounted [38]. …”

Section: Methodsmentioning

confidence: 99%

Increased Levels of Type 1 Interferon in a Type 1 Diabetic Mouse Model Induce the Elimination of B Cells from the Periphery by Apoptosis and Increase their Retention in the Spleen

Badr

Moustafa

Eldien

et al. 2015

Cell Physiol Biochem

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Background: The autoimmune disease type 1 diabetes mellitus (T1D) is associated with a defect in the immune response, which increases susceptibility to infection. We recently demonstrated that prolonged elevated levels of type 1 interferon (IFN) induce lymphocyte exhaustion during T1D. Aims: In the present study, we further investigated the effect of blocking the type I IFN receptor signaling pathway on diabetic dyslipidemia, in which an abnormal lipid profile leads to the exhaustion of B cells and alteration of their distribution and functions. Methods: T1D was induced in a mouse model by an intraperitoneal injection of a single dose (60 mg/kg) of streptozotocin (STZ). Three groups of mice were examined: a non-diabetic control group, a diabetic group and a diabetic group treated with an anti-IFN (alpha, beta and omega) receptor 1 (IFNAR1) blocking antibody to block type I IFN signaling. Results: We observed that induction of T1D was accompanied by a marked destruction of β cells and a reduction in the insulin levels in the diabetic group. Diabetic mice exhibited many changes, including alterations in their lipid profiles, expansion of splenic B cells, increased caspase-3, -8 and -9 activity, and apoptosis in peripheral B cells. Blocking type 1 IFN signaling in diabetic mice significantly returned the insulin and lipid profiles to normal levels, subsequently restored the B cell distribution, and rescued the peripheral B cells from apoptosis. Conclusion: Our data suggest the potential role of type I IFN in mediating diabetic dyslipidemia and an exhausted state of B cells during T1D.

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Initiation of Acquired Immunity in the Lungs of Mice Lacking Lymph Nodes after Infection with Aerosolized Mycobacterium tuberculosis

Cited by 17 publications

References 24 publications

Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis

Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis

Pulmonary mucosal dendritic cells in T-cell activation: implications for TB therapy

Increased Levels of Type 1 Interferon in a Type 1 Diabetic Mouse Model Induce the Elimination of B Cells from the Periphery by Apoptosis and Increase their Retention in the Spleen

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