Reactivation of Latent Tuberculosis Infection in TNF-Deficient Mice

Botha, Tania; Ryffel, Bernhard

doi:10.4049/jimmunol.171.6.3110

Cited by 126 publications

(115 citation statements)

References 78 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…When TNFa production was determined 48 h p.i., significant concentrations were produced by classically activated macrophages, whereas resting and alternatively activated macrophages secreted ten times less TNF-a (not shown). TNF-a as well as IL-12p40 are necessary for the maintenance of host control during persistent tuberculosis [59,60]. Our data further reveal that, like human Mf-2, alternatively activated murine macrophages readily produced MCP-1, IP-10 and MIP-1b upon M. tuberculosis infection.…”

Section: Discussionsupporting

confidence: 57%

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

et al. 2006

View full text Add to dashboard Cite

A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4-and IFN-c-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis.

show abstract

Section: Discussionsupporting

confidence: 57%

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…For example, identifying the CFP10 [32][33][34][35][36][37][38][39] epitope enabled us to show that CFP10-specific CD8 ϩ T cells, which accumulate in the lungs of mice following infection, have cytolytic activity in vivo (1). Elucidating the minimal epitopes presented by class I MHC allows accurate enumeration and characterization of Agspecific CD8 ϩ T cells primed during infection.…”

Section: Antigen-specific Cd8 ؉ T Cells and The Development Of Centramentioning

confidence: 99%

“…Thus, just as CFP10 [32][33][34][35][36][37][38][39] is an immunodominant epitope recognized by CD8 ϩ T cells in mice with the H-2 k haplotype (1), TB10.4 20 -28 is an immunodominant epitope in H-2 d BALB/c mice. TB10.4 20 -28 -specific CD8 ϩ T cells are found both in primary and secondary lymphoid organs, and accumulate in large numbers in the lung and in the bronchoalveolar compartment following aerosol infection with M. tuberculosis.…”

Section: Tb104 20 -28 Is An Immunodominant Ag Following Respiratory mentioning

confidence: 99%

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

Kamath

Woodworth

Behar

2006

The Journal of Immunology

View full text Add to dashboard Cite

Whether true memory T cells develop in the face of chronic infection such as tuberculosis remains controversial. To address this question, we studied CD8+ T cells specific for the Mycobacterium tuberculosis ESAT6-related Ags TB10.3 and TB10.4. The shared epitope TB10.3/10.420–28 is presented by H-2 Kd, and 20–30% of the CD8+ T cells in the lungs of chronically infected mice are specific for this Ag following respiratory infection with M. tuberculosis. These TB10.3/10.420–28-specific CD8+ T cells produce IFN-γ and TNF and express CD107 on their cell surface, which indicates their likely role as CTL in vivo. Nearly all of the Ag-specific CD8+ T cells in the lungs of chronically infected mice had a T effector cell phenotype based on their low expression of CD62L and CD45RB. In contrast, a population of TB10.3/10.420–28-specific CD8+ T cells was identified in the lymphoid organs that express high levels of CD62L and CD45RB. Antibiotic treatment to resolve the infection led to a contraction of the Ag-specific CD8+ T cell population and was accompanied by an increase in the proportion of CD8+ T cells with a central memory phenotype. Finally, challenge of memory-immune mice with M. tuberculosis was accompanied by significant expansion of TB10.3/10.420–28-specific CD8+ T cells, which suggests that these cells are in fact functional memory T cells.

show abstract

“…As an initial validation of the model, knockout simulations were conducted in which either IFN-␥ or TNF-␣ was eliminated from the system, resulting in unrestrained bacterial growth, a consequence seen in the experimental literature (45)(46)(47)(48)(49). In addition, patients suffering with AIDS are at an increased risk of developing active tuberculosis, due in part to a decrease in CD4 T Cells brought about by the disease (50-52).…”

Section: Dendritic Cells (D)mentioning

confidence: 99%

Modeling the immune rheostat of macrophages in the lung in response to infection

Day¹,

Friedman²,

Schlesinger

2009

Proc. Natl. Acad. Sci. U.S.A.

126

View full text Add to dashboard Cite

In the lung, alternatively activated macrophages (AAM) form the first line of defense against microbial infection. Due to the highly regulated nature of AAM, the lung can be considered as an immunosuppressive organ for respiratory pathogens. However, as infection progresses in the lung, another population of macrophages, known as classically activated macrophages (CAM) enters; these cells are typically activated by IFN-␥. CAM are far more effective than AAM in clearing the microbial load, producing proinflammatory cytokines and antimicrobial defense mechanisms necessary to mount an adequate immune response. Here, we are concerned with determining the first time when the population of CAM becomes more dominant than the population of AAM. This proposed ''switching time'' is explored in the context of Mycobacterium tuberculosis (MTb) infection. We have developed a mathematical model that describes the interactions among cells, bacteria, and cytokines involved in the activation of both AAM and CAM. The model, based on a system of differential equations, represents a useful tool to analyze strategies for reducing the switching time, and to generate hypotheses for experimental testing.alternatively activated macrophages ͉ lung innate immunity ͉ mycobacteria tuberculosis

show abstract

Reactivation of Latent Tuberculosis Infection in TNF-Deficient Mice

Cited by 126 publications

References 78 publications

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

Modeling the immune rheostat of macrophages in the lung in response to infection

Contact Info

Product

Resources

About