Macrophage and T Cell Dynamics during the Development and Disintegration of Mycobacterial Granulomas

Egen, Jackson G.; Rothfuchs, Antonio Gigliotti; Feng, Carl G.; Winter, Nathalie; Sher, Alan; Germain, Ronald N.

doi:10.1016/j.immuni.2007.12.010

Cited by 307 publications

(323 citation statements)

References 51 publications

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“…There were also many more CD4 ϩ T cells than CD8ϩ T cells in both the airway lumen and granuloma compartments, supporting the notion that the former is the major effector T-cell subset involved in host defense during mycobacterial infection. 12,33,34 Together, these data reveal a similar immune cellular profile in the airway lumen and the granuloma after pulmonary mycobacterial infection, and indicate that macrophages, dendritic cells, and T cells are the predominant antimycobacterial cellular components.…”

Section: Similar Immune Cellular Composition Observed In Airway Lumenmentioning

confidence: 69%

“…Of note, the host immune responses are only selectively suppressed in the granuloma, as we found the chemokine responses within the granuloma to be largely intact or even more intense than the extragranuloma environment, in keeping with the high demand for continual recruitment of inflammatory cells into the granuloma. 34 Although chemokine responses were similar or elevated in the granuloma, IL-17 responses were decreased, paradoxical to the current belief that IL-17 is involved in the induction of chemokines in some experimental models. 40,51 This provides further support that the granuloma is a differentially regulated immune environment because of the heavy presence of mycobacteria, a phenomenon that likely evolves over the course of the infection.…”

Section: Discussionmentioning

confidence: 87%

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Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN-␥), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.

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Section: Similar Immune Cellular Composition Observed In Airway Lumenmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 87%

Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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“…T cells are then recruited and retained in the granuloma (2). The retention of T cells in the granuloma may depend on IL-17A-induced ICAM-1-LFA-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…TNF-a produced by the infected macrophages is the primary mediator of the granuloma development (2). TNF-a activates macrophages and induces the expression of chemokines and adhesion molecules that are important for the recruitment and retention of cells to the site of infection.…”

mentioning

confidence: 99%

“…TNF-a activates macrophages and induces the expression of chemokines and adhesion molecules that are important for the recruitment and retention of cells to the site of infection. TNF-a-neutralized mice exhibit disorganized granulomas and diffuse cellular infiltration (2)(3)(4). IFN-g is another key cytokine important in controlling mycobacteria in infected macrophages and maturation of functional granulomas.…”

mentioning

confidence: 99%

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Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Yoshida

Umemura

Yahagi

et al. 2010

The Journal of Immunology

355

261

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Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

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Two‐Photon Imaging of the Immune System

et al. 2012

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Two-photon microscopy is a powerful method for visualizing biological processes as they occur in their native environment in real time. The immune system uniquely benefits from this technology as most of its constituent cells are highly motile and interact extensively with each other and with the environment. Two-photon microscopy has provided many novel insights into the dynamics of the development and function of the immune system that could not have been deduced by other methods and has become an indispensible tool in the arsenal of immunologists. In this unit, we provide several protocols for preparation of various organs for imaging by two-photon microscopy that are intended to introduce the new user to some basic aspects of this method.

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Macrophage and T Cell Dynamics during the Development and Disintegration of Mycobacterial Granulomas

Cited by 307 publications

References 51 publications

Pulmonary Mycobacterial Granuloma

Pulmonary Mycobacterial Granuloma

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Two‐Photon Imaging of the Immune System

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