Impaired Protection against <i>Mycobacterium bovis</i> Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

Saito, Kimika; Yajima, Toshiki; Kumabe, Shino; Doi, Takehiko; Yamada, Hisakata; Sad, Subash; Shen, Hao; Yoshikai, Yasunobu

doi:10.4049/jimmunol.176.4.2496

Cited by 32 publications

(21 citation statements)

References 63 publications

(68 reference statements)

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“…The protective role of both IL-15 and NK cells has previously been demonstrated in murine models of intracellular bacterial infections and in models of endotoxic sepsis by systemic E. coli infection (27,(61)(62)(63)(64). However, to date there has been a lack of studies examining the relationship between IL-15 and NK cells in host resistance against pulmonary extracellular bacterial infection.…”

Section: Discussionmentioning

confidence: 99%

“…For example, IL-15 is critically required for the development, survival, and activation of the NK type of innate cell, while it may also have an effect on other innate immune cells (21,(23)(24)(25)(26). Although IL-15 has been shown to play an important role in adaptive immunity against intracellular bacterial pathogens including Listeria monocytogenes and Mycobacterium bovis bacillus Calmette-Guérin (BCG) (27)(28)(29), its role in innate immune responses to extracellular bacterial infection, particularly pulmonary extracellular bacterial or S. aureus infection, still remains to be determined.…”

mentioning

confidence: 99%

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NK Cells Play a Critical Protective Role in Host Defense against Acute ExtracellularStaphylococcus aureusBacterial Infection in the Lung

Small

McCormick

Gill

et al. 2008

The Journal of Immunology

110

104

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Staphylococcus aureus remains a common cause of nosocomial bacterial infections and are often antibiotic resistant. The role of NK cells and IL-15 and their relationship in host defense against extracellular bacterial pathogens including S. aureus remain unclear. We have undertaken several approaches to address this issue using wild type (WT), IL-15 gene knock-out (KO), and NK cell-depleted mouse models. Upon pulmonary staphylococcal infection WT mice had markedly increased activated NK cells, but not NKT or γδ T cells, in the airway lumen that correlated with IL-15 production in the airway and with alveolar macrophages. In vitro exposure to staphylococcal products and/or coculture with lung macrophages directly activated NK cells. In contrast, lung macrophages better phagocytosed S. aureus in the presence of NK cells. In sharp contrast to WT controls, IL-15 KO mice deficient in NK cells were found to be highly susceptible to pulmonary staphylococcal infection despite markedly increased neutrophils and macrophages in the lung. In further support of these findings, WT mice depleted of NK cells were similarly susceptible to staphylococcal infection while they remained fully capable of IL-15 production in the lung at levels similar to those of NK-competent WT hosts. Our study thus identifies a critical role for NK cells in host defense against pulmonary extracellular bacterial infection and suggests that IL-15 is involved in this process via its indispensable effect on NK cells, but not other innate cells. These findings hold implication for the development of therapeutics in treating antibiotic-resistant S. aureus infection.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

NK Cells Play a Critical Protective Role in Host Defense against Acute ExtracellularStaphylococcus aureusBacterial Infection in the Lung

Small

McCormick

Gill

et al. 2008

The Journal of Immunology

110

104

View full text Add to dashboard Cite

show abstract

“…Although IL-15 may be produced in lung tissue (47), IL-15 production in the airways may be limited, since neutralization of IL-15 with an anti-IL-15 mAb did not affect the development of AHR (E. H. Meyer, O. T. Umetsu, and T. Waldman, unpublished observations). The absence or restriction of IL-15 and/or other homeostatic signals in the airways may explain why homeostatic control of iNKT cells does not compensate for loss of CCR4 function and why iNKT cells in the airways are more sensitive to chemotactic control and may behave more like effector cell populations, which expand primarily in response to Ag.…”

Section: Discussionmentioning

confidence: 99%

iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity

Meyer

Wurbel

Staton

et al. 2007

The Journal of Immunology

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iNKT cells are required for the induction of airway hyperreactivity (AHR), a cardinal feature of asthma, but how iNKT cells traffic to the lungs to induce AHR has not been previously studied. Using several models of asthma, we demonstrated that iNKT cells required the chemokine receptor CCR4 for pulmonary localization and for the induction of AHR. In both allergen-induced and glycolipid-induced models of AHR, wild-type but not CCR4−/− mice developed AHR. Furthermore, adoptive transfer of wild-type but not CCR4−/− iNKT cells reconstituted AHR in iNKT cell-deficient mice. Moreover, we specifically tracked CCR4−/− vs wild-type iNKT cells in CCR4−/−:wild-type mixed BM chimeric mice in the resting state, and when AHR was induced by protein allergen or glycolipid. Using this unique model, we showed that both iNKT cells and conventional T cells required CCR4 for competitive localization into the bronchoalveolar lavage/airways compartment. These results establish for the first time that the pulmonary localization of iNKT cells critical for the induction of AHR requires CCR4 expression by iNKT cells.

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“…The latter four mediators all have demonstrated a role in protecting the host against mycobacteria. One example is IL-15, in that IL-15-deficient mice show impaired control in the lungs during BCG infection (47). Conversely, the overexpression of IL-15 in mice enhanced the host immune response against BCG, via the induction of IFN-␥, and increased NK and CD8 ϩ cell responses (48).…”

Section: Discussionmentioning

confidence: 99%

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

Kurtz

Elkins

2015

Clin Vaccine Immunol

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A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses.A lthough it has been more than 90 years since the implementation of immunization with the Mycobacterium bovis BCG vaccine, Mycobacterium tuberculosis is as much of a public health threat today as ever (1). While it is clear that the BCG vaccine has shortcomings, the exact nature of its failure to fully protect adult populations against pulmonary disease still remains a mystery. The lack of understanding of the protective mechanisms needed for the successful control of M. tuberculosis impedes the design and testing of next-generation novel vaccine candidates (2-4).Much work has already been done to elucidate the protective mechanisms involved in the primary and secondary host responses to M. tuberculosis. Several immune components are integral to the primary immune response to M. tuberculosis, as has been demonstrated in both humans and mice. Interferon gamma (IFN-␥) is important for infection control in humans, as individuals with deficiencies in IFN-␥ signaling pathways are more susceptible to disseminated BCG and infections caused by nontuberculous mycobacteria (NTM) (5). In murine studies, IFN-␥ is essential for controlling the growth of the bacteria, as mice deficient in IFN-␥ succumb quickly to infection (6, 7).A primary source of IFN-␥ is activated CD4 ϩ T cells, which are themselves important for controlling M. tuberculosis infections. The role of CD4 ϩ T cells has been clearly demonstrated in humans in the context of HIV and associated T-cell deficiencies, as these patients are h...

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Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

Cited by 32 publications

References 63 publications

NK Cells Play a Critical Protective Role in Host Defense against Acute ExtracellularStaphylococcus aureusBacterial Infection in the Lung

NK Cells Play a Critical Protective Role in Host Defense against Acute ExtracellularStaphylococcus aureusBacterial Infection in the Lung

iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

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