Macrophage-Derived Nitric Oxide Inhibits the Proliferation of Activated T Helper Cells and Is Induced during Antigenic Stimulation of Resting T Cells

Veen, Roel C. van der; Dietlin, Therese A.; Gray, J. Dixon; Gilmore, Wendy

doi:10.1006/cimm.1999.1597

Cited by 53 publications

(45 citation statements)

References 47 publications

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“…The difference between the two studies may be explained by the use of a single high dose of preformed ONOO Ϫ , which also induced apoptosis in activated T cells (43), whereas in the current system, NO and ONOO Ϫ formation occurs gradually, with a low concentration at any given time (estimated at Ͻ5 nM) and a limited effect on cell viability (34,44).…”

Section: Discussionmentioning

confidence: 96%

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

Veen

Dietlin

Hofman

et al. 2000

The Journal of Immunology

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NO, which suppresses T cell proliferation, may be inactivated by superoxide (O2−) due to their strong mutual affinity. To examine this possibility, preactivated Th clones were cocultured with stimulated macrophages. PMA neutralized the inhibitory activity of NO, which was dependent on extracellular O2− production. In contrast, macrophages from p47phox −/− (pKO) mice, which lack functional NADPH oxidase, retained their NO-dependent inhibition of T cell proliferation upon stimulation with PMA, indicating that NADPH oxidase is the major source of NO-inactivating O2− in this system. To examine the NO-O2− interaction in vivo, the role of NADPH oxidase in experimental autoimmune encephalomyelitis was studied in pKO mice. No clinical or histological signs were observed in the pKO mice. Neither a bias in Th subsets nor a reduced intensity of T cell responses could account for the disease resistance. Although spleen cells from pKO mice proliferated poorly in response to the immunogen, inhibition of NO synthase uncovered a normal proliferative response. These results indicate that NO activity may play a critical role in T cell responses in pKO mice and that in normal spleens inhibition of T cell proliferation by NO may be prevented by simultaneous NADPH oxidase activity.

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Section: Discussionmentioning

confidence: 96%

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

Veen

Dietlin

Hofman

et al. 2000

The Journal of Immunology

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“…Inhibition of T-cell proliferation by tumour-derived MDSC and inflammatory monocytes in experimental autoimmune encephalomyelitis has been reported to be the result of the production of NO. 27,28 Since TNFR1…”

Section: Ot-ii T Cells That Had Been Stimulated By Tnfr1mentioning

confidence: 99%

TNFR1 signalling is a critical checkpoint for developing macrophages that control of T‐cell proliferation

et al. 2010

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SummaryMacrophages (Mu) are professional antigen-presenting cells, but when they accumulate at sites of inflammation, they can inhibit T-cell proliferation. In experimental autoimmune uveoretinitis, this limits the expansion of T cells within the target organ. To define requirements for the elaboration of this outcome, we have generated populations of Mu in vitro that could also regulate T-cell responses; stimulating CD4 + T-cell activation and cytokine production, but simultaneously suppressing T-cell proliferation. When T cells are removed from the influence of such cells, normal T-cell responses are restored. We show that tumour necrosis factor 1 (TNFR1) signalling is a critical checkpoint in the development of such Mu, as TNFR1 )/) Mu are unable to suppress T-cell proliferation. This deficit in antigen-presenting cells results in a lack of production of prostaglandin E 2 (PGE 2 ) and nitric oxide, which are critical effector mechanisms that inhibit T-cell division. However, TNFR1 signalling is not required for the inhibitory function of Mu because we could circumvent the requirement for this receptor, by maturing Mu in the presence of exogenous interferon-c and PGE 2 . This produced TNFR1 )/) Mu that inhibited T-cell proliferation and indicates that TNFR1 delivers a signal that is necessary for the development but not the execution of this function.

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“…RBP-3 161-180 (SGIPYIISYLHPGNTILHVD) and hRBP-3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (GPTH LFQPSLVLDMAKVLLD) peptide was synthesized by Sigma Genosys to 95% purity. Complete tissue culture medium was DMEM (without phenol red) supplemented with 10% v/v FCS, 100 U/ml penicillin, 100 g/ml streptomycin, 2 mM L-glutamine, 1 mM sodium pyruvate, and 5 M 2-ME (all Invitrogen).…”

Section: Mice and Reagentsmentioning

confidence: 99%

“…As well as initiating tissue damage, NO has also been shown to act on T cells, limiting their proliferative responses (15). This raised the question of whether or not NO-producing macrophages, present within the eye during EAU, limited local T cell proliferation and whether or not this regulation was TNFR1-dependent.…”

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confidence: 99%

TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis

Raveney¹,

Copland

Dick

et al. 2009

The Journal of Immunology

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Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b+ macrophages and CD4+ T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b+ myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-γ and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-γ and autocrine TNF-α signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction.

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Macrophage-Derived Nitric Oxide Inhibits the Proliferation of Activated T Helper Cells and Is Induced during Antigenic Stimulation of Resting T Cells

Cited by 53 publications

References 47 publications

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice

TNFR1 signalling is a critical checkpoint for developing macrophages that control of T‐cell proliferation

TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis

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