Lack of inducible nitric oxide synthase activity in T cell clones and T lymphocytes from naive and <i>Leishmania major</i>‐infected mice

Thüring, H; Stenger, Steffen; Gmehling, Daniela; Röllinghoff, Martin; Bogdan, Christian

doi:10.1002/eji.1830251205

Cited by 23 publications

(11 citation statements)

References 40 publications

(13 reference statements)

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“…1, NO production could be augmented by addition of splenic T cells to levels similar to that induced by IFN-␥ and LPS. On the other hand, T cells incubated without macrophages failed to produce NO (data not shown), confirming previous reports that T cells do not produce NO (39). To define the optimal T cell/macrophage ratio for activation, we cocultured bone marrow-derived macrophages with increasing numbers of naive anti-CD3-treated T cells.…”

Section: Tnfrp55p75supporting

confidence: 86%

Activated T Cells Induce Macrophages To Produce NO and ControlLeishmania majorin the Absence of Tumor Necrosis Factor Receptor p55

Nashleanas

Scott

2000

Infect Immun

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The ability to activate macrophages in vitro for nitric oxide production and killing of Leishmania major parasites is dependent on tumor necrosis factor, although L. major-infected mice lacking the TNF receptor p55 (TNFRp55 ؊/؊ mice) or both the TNFRp55 and TNFRp75 (TNFRp55p75 ؊/؊ mice) are able to produce NO in vivo and eliminate the parasites. Here we report that activated T cells cocultured with macrophages results in TNFR-independent activation sufficient to control parasites and that both CD40/CD40L and LFA-1 contribute to T-cell-mediated macrophage activation. Thus, anti-CD3-stimulated T cells activated TNFR-deficient macrophages, while T cells from CD40L ؊/؊ mice were partially defective in triggering NO production by TNFRp55p75 ؊/؊ macrophages. Moreover, in the presence of gamma interferon, anti-CD40 monoclonal antibody (MAb) activated TNFR-deficient macrophages. Finally, MAb blockade of LFA-1 completely inhibited macrophage NO production. Our data indicate that T cells can activate macrophages in the absence of TNF, thus providing a mechanism for how TNFR-deficient mice can control intracellular pathogens.The protozoan parasite Leishmania major infects mononuclear phagocytes, and control of infection depends on adequate activation of the infected macrophages to kill parasites and inhibit their replication (15). In vitro studies with murine macrophages revealed that soluble factors secreted by activated T cells mediate activation of macrophages to produce nitric oxide (NO), resulting in killing or control of L. major parasites (2). Macrophage activation by soluble factors (cytokines) depends on gamma interferon (IFN-␥) as well as tumor necrosis factor (TNF) (11,12,19,41). Optimal NO production occurs in macrophages via upregulation of inducible nitric oxide synthase (iNOS) mRNA, which is itself optimally induced when IFN regulatory factor 1 is upregulated by IFN-␥, and NF-B is activated by a second signal (22,32). TNF has been shown to be a major NF-B-activating signal for macrophage activation. Thus, IFN-␥ and autocrine secretion of TNF by macrophages are sufficient to mediate production of NO and killing of L. major parasites (11,18).We previously demonstrated that macrophages derived from TNFR (TNF receptor)p55 Ϫ/Ϫ or TNFRp55p75 Ϫ/Ϫ mice failed to produce NO and control parasites upon stimulation with IFN-␥ in vitro, whereas TNFRp75 Ϫ/Ϫ mice lacked this defect (25). This suggested that the TNF dependence of in vitro macrophage activation to produce NO and kill parasites was mediated by the TNFRp55. However, work with receptor knockouts, soluble TNFR-Ig (immunoglobulin) overexpression transgenics, and neutralizing antibodies show that TNF is not required for in vivo control of parasites, for the development of the type 1 IFN-␥ response to antigen restimulation, or for upregulation of iNOS at the site of infection in vivo (9,20,25,42,44). These data suggest that an in vivo mechanism exists that permits macrophages to produce NO and control parasites independent of TNF.Since T cells are present in the le...

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Section: Tnfrp55p75supporting

confidence: 86%

Activated T Cells Induce Macrophages To Produce NO and ControlLeishmania majorin the Absence of Tumor Necrosis Factor Receptor p55

Nashleanas

Scott

2000

Infect Immun

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“…2E). This is in line with the lack of NOS2 in these cells (25). Thus, NOS2-derived NO is required for the activation of NK cells, but not T cells, by IL-12.…”

supporting

confidence: 82%

Requirement for Type 2 NO Synthase for IL-12 Signaling in Innate Immunity

Diefenbach¹,

Schindler²,

Röllinghoff³

et al. 1999

Science

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177

150

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Interleukin-12 (IL-12) and type 2 NO synthase (NOS2) are crucial for defense against bacterial and parasitic pathogens, but their relationship in innate immunity is unknown. In the absence of NOS2 activity, IL-12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer (NK) cells for cytotoxicity or interferon-gamma (IFN-gamma) release, and failed to activate Tyk2 kinase and to tyrosine phosphorylate Stat4 (the central signal transducer of IL-12) in NK cells. Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.

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“…In the mouse, Thl cells can be activated to produce large amounts of NO which can inhibit the secretion of IL-2 and IFN-7 by Thl cells, thus acting as an autoregulator of the immune response [27] and possibly altering the balance of Thl and Th2 cells. However, others have been unable to demonstrate T-cell synthesis of NO [28]. B-cells may also be a source of NO, and in humans it has been reported that Epstein-Barr virus-transformed B-cells and cell lines from Burkitt's lymphoma express iNOS [29].…”

Section: No In the Generation Of The Immune Responsementioning

confidence: 99%