Distinct and Nonredundant In Vivo Functions of TNF Produced by T Cells and Macrophages/Neutrophils

Grivennikov, Sergei I.; Tumanov, Alexei V.; Liepinsh, Dmitry J.; Kruglov, Andrey; Marakusha, B.I.; Shakhov, Alexander N.; Murakami, Takaya; Drutskaya, Ludmila N.; Förster, Irmgard; Clausen, Björn E.; Tessarollo, Lino; Ryffel, Bernhard; Kuprash, Dmitry V.; Nedospasov, Sergei A.

doi:10.1016/j.immuni.2004.11.016

Cited by 225 publications

(256 citation statements)

References 58 publications

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“…Our results are consistent with a recent report that showed an important role for T cell-derived TNF-␣, which found that TNF-␣ knocked out in the T cell lineage resulted in increased susceptibility to LM challenge, as well as inability to control bacterial load by day 4 p.i. (43). Moreover, our results are consistent with the implication that T cell-derived TNF-␣ possesses a distinct function in host defense by providing protection against high bacterial load (43), constituting a second line of defense.…”

Section: Discussionsupporting

confidence: 90%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

137

129

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Naive T cells require costimulation for robust Ag-driven differentiation and survival. Members of the TNFR family have been shown to provide costimulatory signals conferring survival at distinct phases of the T cell response. In this study, we show that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo. We demonstrate using the MHC class I-restricted 2C TCR and MHC class II-restricted AND TCR transgenic systems that TNFR2 regulates the threshold for clonal expansion of CD4 and CD8 T cell subsets in response to cognate Ag. Using a novel recombinant Listeria monocytogenes (rLM) expressing a secreted form of the 2C agonist peptide (SIY) to investigate the role of TNFR2 for T cell immunity in vivo, we found that TNFR2 controls the survival and accumulation of effector cells during the primary response. TNFR2−/− CD8 T cells exhibit loss of protection from apoptosis that is correlated with diminished survivin and Bcl-2 expression. Null mutant mice were more susceptible to rLM-SIY challenge at high doses of primary infection, correlating with impaired LM-specific T cell response in the absence of TNFR2-mediated costimulation. Moreover, the resulting memory pools specific for SIY and listeriolysin O epitopes derived from rLM-SIY were diminished in TNFR2−/− mice. Thus, examination of Ag-driven T cell responses revealed a hitherto unknown costimulatory function for TNFR2 in regulating T cell survival during the differentiation program elicited by intracellular pathogen in vivo.

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Section: Discussionsupporting

confidence: 90%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

137

129

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“…We previously established that the cholinergic antiinflammatory pathway regulates TNF production in the spleen (12), but the cellular source of spleen TNF during endotoxemia was previously unknown. Macrophages, a component of the reticuloendothelial system, are a major source of TNF in endotoxemia (18). TNF was detected by immunofluorescence 30 min after endotoxin administration in the red pulp and the marginal zone (MZ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Rosas-Ballina¹,

Ochani²,

Parrish³

et al. 2008

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

597

569

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The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

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“…2,3 Furthermore, TNF derived from hematopoietic cells, especially macrophages/neutrophils, plays a critical role in inflammatory reactions 20,33 and Listeria infection. 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.…”

Section: Discussionmentioning

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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Distinct and Nonredundant In Vivo Functions of TNF Produced by T Cells and Macrophages/Neutrophils

Cited by 225 publications

References 58 publications

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

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