Gamma Interferon-Induced T-Cell Loss in Virulent<i>Mycobacterium avium</i>Infection

Florido, Mário; Pearl, John E.; Solache, Alejandra; Borges, Marisa; Haynes, Laura; Cooper, Andrea M.; Appelberg, Rui

doi:10.1128/iai.73.6.3577-3586.2005

Cited by 43 publications

(58 citation statements)

References 38 publications

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“…It was shown that neutralization of IL-12 or IFN-␥ as well as depletion of CD4 ϩ T cells was able to prevent the disintegration of granulomas and the death of TNFR1-deficient mice infected with Mycobacterium avium, showing that hypersecretion of IFN-␥ by the latter T cell population may be the final mediator in the induction of this type of pathology (11). IFN-␥ has likewise been implicated as a primary mediator of other immunopathological conditions associated to chronic mycobacteriosis such as the induction of caseous necrosis in granulomas and the development of severe lymphopenia (21)(22)(23). However, the immediate effector mechanisms have not been identified for any of these phenomena.…”

Section: Characterization Of the Deregulated Immune Activationmentioning

confidence: 99%

Characterization of the Deregulated Immune Activation Occurring at Late Stages of Mycobacterial Infection in TNF-Deficient Mice

Florido¹,

Appelberg

2007

The Journal of Immunology

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In the absence of TNF, mice infected with Mycobacterium avium suffer a peculiar disintegration of the granulomas, with extensive apoptosis and necrosis of their cells, occurring during the course of the infection and leading to the death of the animals within a few days of its onset. The survival time depends on the virulence of the infecting strain as well as on the dose and route of infection. Intravenously infected mice developed the typical lesions in hepatic granulomas whereas aerosol-infected animals developed them in the lung granulomas. At the onset of the development of pulmonary granuloma disintegration, extensive expansion of T cells, with intense up-regulation of activation markers, massive exacerbation of their ability to secrete IFN-γ, and increased cytotoxic activity of both CD4+ and CD8+ T cells were observed. Forced expression of Bcl2 did not prevent the early death of infected TNF-deficient mice leading merely to a modest increase in survival times. The expression of the FasL on T cells was not affected but there was an intense up-regulation of the TRAIL in T cells and, in particular, myeloid cells. We thus show that an exacerbated immune response occurs in TNF-deficient hosts during M. avium infections that leads to enhanced IFN-γ production and late up-regulation of TRAIL which may contribute to granuloma disintegration.

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Section: Characterization Of the Deregulated Immune Activationmentioning

confidence: 99%

Characterization of the Deregulated Immune Activation Occurring at Late Stages of Mycobacterial Infection in TNF-Deficient Mice

Florido¹,

Appelberg

2007

The Journal of Immunology

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“…Interestingly, infection of immunocompetent C57BL/6 mice with a high dose of the same M. avium strain did not induce necrotic granulomas. The explanation for this result lies in the fact that in this type of infection, severe lymphopenia is induced and granulomas do not get to be as large as those observed when T cells are spared, i.e., in low-dose infections (13).…”

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confidence: 97%

Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

et al. 2015

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eThe establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain of Mycobacterium avium. In this work, a mouse strain deleted of the hypoxia inducible factor 1␣ (HIF-1␣) under the Cre-lox system regulated by the lysozyme M gene promoter was used to determine the relevance of HIF-1␣ in the caseation of granulomas. The genetic ablation of HIF-1␣ in the myeloid lineage causes the earlier emergence of granuloma necrosis and clearly induces an impairment of the resistance against M. avium infection coincident with the emergence of necrosis. The data provide evidence that granulomas become hypoxic before undergoing necrosis through the analysis of vascularization and quantification of HIF-1␣ in a necrotizing mouse model. Our results show that interfering with macrophage adaptation to hypoxia, such as through HIF-1␣ inactivation, accelerates granuloma necrosis.T he main pathological feature of human tuberculosis is the induction by Mycobacterium tuberculosis of granulomas which undergo central necrosis (caseous necrosis) (1). The mechanisms underlying the latter phenomenon are not clear, but it is generally accepted that caseation plays an essential role in the pathogenesis and dissemination of the infection. Caseous necrosis and cavitation during infection by M. tuberculosis is more prominent in rabbits and guinea pigs than in mice (2). Nevertheless, human-like pathology, as central granuloma necrosis and associated hypoxia, can be obtained in M. tuberculosis-infected I/StSnEgYCit, C3HeB/ FeJ, or IL-13-overexpressing C57BL/6 mouse strains (3-5). Confluent necrotic granulomas also are observed in mice deficient in gamma interferon (IFN-␥) or the type 1 tumor necrosis factor (TNF) receptor (2, 6, 7). However, the fact that immunodeficient human hosts, namely, AIDS patients, tend to present forms of tuberculosis with granulomas lacking necrotic features suggests that necrosis depends on the immune response (8).We have shown that mice infected with a small inoculum of M. avium ATCC 25291 establish a chronic and progressive infection characterized by the formation of discrete granulomas, which gradually increase in size and undergo central necrosis within a few months (9). This requires CD4 ϩ T cells as well as an intact interleukin-12 (IL-12)/IFN-␥ cytokine axis (9) but is independent...

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“…Many studies have shown that mice with a deficiency of Fas, mice lacking both Fas and TNF-␣, and mice lacking TNFR1 have impaired apoptosis or deletion of activated peripheral T cells (4 -10). Many other studies have reported normal apoptosis or deletion of activated T cells in mice with a deficiency of Fas, mice with deficiencies of both TNFR1 and Fas, and even in mice with triple deficiencies of TNFR1, Fas, and TNFR2 (11)(12)(13)(14)(15). These studies highlight a controversy about whether death receptors such as Fas and TNFR1 play essential roles during apoptosis of activated T cells.…”

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IFN-γ Acts Directly on Activated CD4+ T Cells during Mycobacterial Infection to Promote Apoptosis by Inducing Components of the Intracellular Apoptosis Machinery and by Inducing Extracellular Proapoptotic Signals

McKinstry

Swain

et al. 2007

The Journal of Immunology

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Despite many studies, the regulation of CD4+ T cell apoptosis during the shutdown of immune responses is not fully understood. We have investigated the molecular mechanisms of IFN-γ in regulating apoptosis of CD4+ T cells during bacillus Calmette-Guérin (BCG) infection of mice. Our data provide new insight into the regulation of CD4+ T cell apoptosis by IFN-γ. As CD4+ T cells responded to BCG infection, there was a coordinated increase in IFN-γ production by effector CD4+ T cells and a coordinated IFN-γ-dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4+ T cells. Unexpectedly, IFN-γ up-regulated transcripts and protein expression of Bcl-2, Bax, Bim, Bid, Apaf-1, and caspase-9 in activated CD4+ T cells—components of the apoptosis machinery that are involved in promoting mitochondrial damage-mediated apoptosis. Wild-type, but not IFN-γ knockout, CD4+ T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN-γ also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFR1. Cell-extrinsic apoptosis signals from TNF-α, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4+ T cells. Moreover, activated CD4+ T cells from BCG-infected DR5, TNFR1, and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN-γ promotes apoptosis of CD4+ T cells during BCG infection as follows: 1) by sensitizing CD4+ T cells to apoptosis by inducing intracellular apoptosis molecules and 2) by inducing cell-extrinsic apoptosis signals that kill CD4+ effector T cells.

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Gamma Interferon-Induced T-Cell Loss in VirulentMycobacterium aviumInfection

Cited by 43 publications

References 38 publications

Characterization of the Deregulated Immune Activation Occurring at Late Stages of Mycobacterial Infection in TNF-Deficient Mice

Characterization of the Deregulated Immune Activation Occurring at Late Stages of Mycobacterial Infection in TNF-Deficient Mice

Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

IFN-γ Acts Directly on Activated CD4+ T Cells during Mycobacterial Infection to Promote Apoptosis by Inducing Components of the Intracellular Apoptosis Machinery and by Inducing Extracellular Proapoptotic Signals

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