Contribution of Transmembrane Tumor Necrosis Factor to Host Defense against Mycobacterium bovis Bacillus Calmette-Guerin and Mycobacterium tuberculosis Infections

Olleros, Maria L.; Guler, Reto; Vesin, Dominique; Parapanov, Roumen; Marchal, G; Martinez-Soría, Eduardo; Corazza, Nadia; Pache, Jean–Claude; Mueller, Christoph; García, Irene

doi:10.1016/s0002-9440(10)62331-0

Cited by 79 publications

(61 citation statements)

References 44 publications

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“…In the presence of only memTNF, there was significant overproduction of chemokines during primary infection. Transient overproduction of IL-12(p40) was also observed in M. tuberculosis-infected memTNF mice (32,33). This dysregulated inflammatory response was the likely cause of increased inflammatory lesions containing neutrophils and necrotic tissue destruction in the lung (Mycobacterium) or liver (Listeria) of infected animals, resulting in mortality.…”

Section: Discussionmentioning

confidence: 91%

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Cowley

Sedgwick

Elkins

2007

The Journal of Immunology

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During primary infection with intracellular bacteria, the membrane-associated form of TNF provides some TNF functions, but the relative contributions during memory responses are not well-characterized. In this study, we determined the role of T cell-derived secreted and membrane-bound TNF (memTNF) during adaptive immunity to Francisella tularensis live vaccine strain (LVS). Although transgenic mice expressing only the memTNF were more susceptible to primary LVS infection than wild-type (WT) mice, LVS-immune WT and memTNF mice both survived maximal lethal secondary Francisella challenge. Generation of CD44high memory T cells and clearance of bacteria were similar, although more IFN-γ and IL-12(p40) were produced by memTNF mice. To examine T cell function, we used an in vitro tissue coculture system that measures control of LVS intramacrophage growth by LVS-immune WT and memTNF-T cells. LVS-immune CD4+ and CD8+ T cells isolated from WT and memTNF mice exhibited comparable control of LVS growth in either normal or TNF-α knockout macrophages. Although the magnitude of CD4+ T cell-induced macrophage NO production clearly depended on TNF, control of LVS growth by both CD4+ and CD8+ T cells did not correlate with levels of nitrite. Importantly, intramacrophage LVS growth control by CD8+ T cells, but not CD4+ T cells, was almost entirely dependent on T cell-expressed TNF, and required stimulation through macrophage TNFRs. Collectively, these data demonstrate that T cell-expressed memTNF is necessary and sufficient for memory T cell responses to this intracellular pathogen, and is particularly important for intramacrophage control of bacterial growth by CD8+ T cells.

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Section: Discussionmentioning

confidence: 91%

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Cowley

Sedgwick

Elkins

2007

The Journal of Immunology

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“…34 For mycobacterial infection a partial protective effect has been shown by membrane TNF in the same noncleavable membrane TNF mouse 35 and in a different transgenic mouse model. 13 The partial protection generated in mem-TNF mice could indicate local cell-to-cell TNF signaling by membrane-expressed TNF on T cells or macrophages at the site of infection, leading to a partial activation of the immune cells. Indeed, for the resistance to intracellular pathogens TNF must be produced locally, 36 whereas exogenous systemically administered TNF is ineffective.…”

Section: Discussionmentioning

confidence: 99%

“…8 -10 The transgenic overexpression of membrane TNF has demonstrated an in vivo role in the control of LM and mycobacterial infection. [11][12][13] However, these models were potentially nonphysiological as transgenic expression of a membrane-only form of TNF results in artificially high and nonselective expression of membrane TNF. The recent generation of mice with functional, normally regulated and expressed membrane-bound TNF, obtained by knocking-in an uncleavable ⌬1-9, K11E TNF allele (mem-TNF mice), represents a major advance and allows interesting insights in the role of membrane TNF in lymphoid structure development and inflammation.…”

mentioning

confidence: 99%

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Torres

Janot

Quesniaux

et al. 2005

The American Journal of Pathology

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Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF ؊/؊ ) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (10 4 CFU) but succumbed at a higher dose of infection (10 5 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF ؊/؊ , mice protected TNF ؊/؊ mice from fatal infection. Taken Protective immunity to Listeria monocytogenes (LM) infection, both in humans and experimental animals, is based on orchestrated action of T cells, macrophages, and cytokines, including interferon (IFN)-␥, interleukin (IL)-12, and tumor necrosis factor (TNF). 1 A critical role for TNF in anti-LM defense is inferred from neutralization and gene deletion experiments in mice. 2,3 In addition, the TNFrelated cytokines lymphotoxin (LT)-␣ and LT-␤ are also required to control LM infection. 4 Both secreted TNF and LT-␣ signal through p55 and p75 TNF receptors (TNFR1 and TNFR2, respectively). The cell-bound LT-␣␤ heterotrimers recognize the LT-␤R. TNF-R1 signaling appears to be critical for the control of LM infection 2,3 and LT-␤R also plays a distinct role, while the contribution of TNFR2 is less well defined.TNF is expressed by a variety of cells, including macrophages and T cells, and is a major regulator of inflammation and leukocyte trafficking. 5 TNF is first produced as an integral membrane protein and is subsequently cleaved by the metalloproteinase-disintegrin TACE (TNF-␣ converting enzyme) 6,7 into the secreted trimeric TNF. Although the role of TNF in controlling intracellular bacterial infections is uncontested, the function of membrane TNF in host resistance is less understood.Several biological functions of membrane TNF have been described, such as cytotoxicity, polyclonal activation of B cells, induction of IL-10 by monocytes, induction of chemokines, and ICAM-1 expression on endothelial cells. 8 -10 The transgenic overexpression of membrane TNF has demonstrated an in vivo role in the control of LM and mycobacterial infection. [11][12][13] However, these models were potentially nonphysiological as transgenic expression of a membrane-only form of TNF results in artificially high and nonselective expression of membrane TNF. The recent generation of mice with functional, normally regulated and expressed membrane-bound TNF, obtained by knocking-in an uncleavable ⌬1-9, K11E TNF allele (mem-TNF mice), represents a major advance and allo...

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“…Regulation of granuloma formation is poorly understood, although TNF-␣ has a key role in animal and human studies (1)(2)(3)(4)(5). Chemokines, small (8 -10kDa) peptides involved in cell recruitment to sites of inflammation, are implicated in granuloma formation and maintenance (6).…”

Section: T Uberculosis (Tb)mentioning

confidence: 99%

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

O’Kane

Boyle

Horncastle

et al. 2007

The Journal of Immunology

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CXCL8 is a chemokine that is implicated in the formation of tuberculous (TB) granulomas and in immunity to Mycobacterium tuberculosis (Mtb). Fibroblast chemokine secretion is important for modulating inflammatory responses in chronic lung disease and inflammatory arthritis but has not been investigated in the pathophysiology of TB. In this study, we used a cellular model to examine monocyte/macrophage-dependent stimulation of fibroblasts by Mtb in the regulation of chemokine secretion, particularly that of CXCL8. Human lung fibroblasts grown in collagen were stimulated with conditioned medium from Mtb-infected monocytes (CoMTb). CoMTb-induced prolonged dose-dependent, p38-mediated expression of stable CXCL8 mRNA by fibroblasts accompanied by a >10-fold increase in CXCL8 secretion (487 ± 88 ng/ml vs 48.6 ± 34 ng/ml in controls) at 120 h. Fibroblasts strongly expressed CXCL8 in vivo in human TB granulomas. Inhibition of TNF-α or IL-1 in CoMTb abrogated the induction of CXCL8 at a pretranscriptional level. CXCL8 secretion was NF-κB, C/EBP, and JNK dependent. Sustained NF-κB activation was demonstrated beyond 24 h in response to CoMTb. Exogenous CXCL8 reduced the survival of Mtb within macrophages, and inhibition of CXCL8 was associated with intracellular mycobacterial proliferation. These data show that fibroblasts have a previously unrecognized role in modulating inflammation in TB by their CXCL8-dependent contribution to cell recruitment and mycobacterial killing within the granuloma.

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Contribution of Transmembrane Tumor Necrosis Factor to Host Defense against Mycobacterium bovis Bacillus Calmette-Guerin and Mycobacterium tuberculosis Infections

Cited by 79 publications

References 44 publications

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

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