Divergent Roles for p55 and p75 Tumor Necrosis Factor Receptors in the Pathogenesis of MOG35-55-Induced Experimental Autoimmune Encephalomyelitis

Suvannavejh, Graig C.; Lee, Hae Ock; Padilla, Josette; Canto, Mauro C. Dal; Barrett, Terrence A.; Miller, Stephen D.

doi:10.1006/cimm.2000.1706

Cited by 145 publications

(120 citation statements)

References 57 publications

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“…Because tmTNF-a has a higher affinity for TNFR2 than sTNF-a (13), this may also account for the difference between two forms of TNF-a in the activation of MDSCs. Furthermore, in contrast to TNFR1, TNFR2 is considered to be associated with a negative regulation of inflammatory pathological process (44,45). It has been reported that TNFR2-expressing CD4 + Foxp3 + Tregs comprise ∼40% of peripheral Tregs in normal mice and represent the maximally suppressive subset of Tregs (46).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

et al. 2014

The Journal of Immunology

153

144

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It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α–induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α–mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-β, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

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Section: Discussionmentioning

confidence: 99%

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

et al. 2014

The Journal of Immunology

153

144

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“…Thus, where do we stand at the moment? Il12p35 À/À mice, Il12rb2 À/À mice, Ifng À/À mice, Ifngr À/À mice, Il17 À/À mice, Il21 À/À mice, Il21r À/À mice, Il22 À/À mice, Tnf À/À mice, and Tnfr(p75) À/À mice are not resistant to EAE although all of these cytokines are either required for the development of Th1 responses or are signature effector cytokines of Th1 or Th17 cells [31][32][33]121,133,134,[169][170][171]. On the other hand, Il23p19 À/À mice, Il23r À/À mice, Il6 À/À mice, T cell conditional gp130 À/À mice, and Gmcsf À/À mice are resistant to EAE corroborating the importance of the IL-23/Th17 axis for the development of chronic inflammation and autoimmunity [36,87,142,172,173].…”

Section: Discussionmentioning

confidence: 99%

“…In line with these findings, Tnfr1(p55) À/À mice were totally resistant to EAE. However, Tnfr2(p75) À/À mice exhibited exacerbated EAE, with increased Th1 cytokine production, and increased infiltration of CD4 + T cells and macrophages in the CNS [133]. Also, mice deficient for TNF were not protected from EAE; they even developed a more severe variant of EAE, characterized by extensive inflammation and demyelination [134].Indeed, after toxic demyelination, Tnfr2(p75) À/À mice showed reduced proliferation of oligodendrocyte precursor cells and thus, impaired remyelination as compared with wild type littermates or Tnfr1(p55) À/À mice suggesting that TNF promotes remyelination by acting directly on TNFR2 + oligodendrocyte precursors [135].Taken together, these observations support the hypothesis that TNF may not only be a myelinolytic effector molecule of exaggerated Th1 responses but also have a role in immunoregulation (by inducing apoptosis) and tissue repair (by modulating remyelination).…”

Section: Tnfmentioning

confidence: 95%

Cytokines and effector T cell subsets causing autoimmune CNS disease

2011

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a b s t r a c tAlthough experimental autoimmune encephalomyelitis (EAE) is limited in its potency to reproduce the entirety of clinical and histopathologic features of multiple sclerosis (MS), this model has been successfully used to prove that MS like autoimmunity in the CNS is orchestrated by autoantigen specific T cells. EAE was also very useful to refute the idea that IFN-c producing T helper type 1 (Th1) cells were the sole players within the pathogenic T cell response. Rather, ''new'' T cell lineages such as IL-17 producing Th17 cells or IL-9 producing Th9 cells have been first discovered in the context of EAE. Here, we will summarize new concepts of early and late T cell plasticity and the cytokine network that shapes T helper cell responses and lesion development in CNS specific autoimmunity.

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“…TNF has been strongly implicated in the pathogenesis of MS; however, it appears that TNF is also able to down-regulate a deleterious autoimmune T-cell response against myelin antigens. Indeed, in EAE, it has been proposed that the deleterious effects of TNF are mediated by TNFR1 and that the immunosuppressive functions of TNF may be exerted via TNFR2 [32,33]. In the cecal ligation and puncture model of polymicrobial sepsis, it was further suggested that TNFR1 is responsible for much of the TNF-induced pathology, whereas TNFR2 mediates protective effects [34].…”

Section: Discussionmentioning

confidence: 99%

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

et al. 2009

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TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4 + T-cell transfer model of colitis using TNFR2 À/À or WT mice as donors of colitogenic CD4 + CD45RB hi T cells for transfer into syngeneic RAG2 À/À or RAG2 À/À TNFR2 À/À recipient mice. Although the absence of TNFR2 expression by nonlymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2 À/À CD4 + T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2 À/À CD4 1 T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2 À/À CD4 1 T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.Key words: CD4 1 T cells Á Inflammation Á Intestinal immunity Á TNF Introduction TNF plays a fundamental role in immunity and inflammation based on its pleiotropic effects on differentiation, growth and apoptotic cell death of both immune and non-immune cell subsets [1,2]. It is well established that TNF is also critically involved in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, MS and inflammatory bowel diseases (IBD) [3]. Monocytes and macrophages are the main producers of TNF, but T and B lymphocytes and also mast cells can produce significant amounts of TNF. Interestingly, intestinal cell lines are induced to synthesize TNF upon infection with invasive bacterial strains [4]. TNF mediates its functions by binding as a trimer to either TNF receptor (TNFR) 1 or 2. The binding of TNF trimer to the preassembled TNFR complex leads to conformational changes of the receptors facilitating signal transduction through rapid recruitment of downstream signaling molecules. Both receptors have distinct signal transduction pathways and mediate distinct cellular responses [1,[5][6][7][8][9][10]. The 55 kDa receptor, TNFR1 (also known as p55, p60, TNFRSF1a, CD120a) is expressed on most cell types. The intracellular domain of TNFR1 contains a death domain (DD) that leads to apoptosis through caspase activation. TNFR1 signaling can also mediate transcription of anti-apoptotic proteins, inflammatory cytokines and chemokines through activation of NF-kB. The 75 kDa receptor, TNFR2 (also known as p75, p80, TNFRSF1b, CD120b), is Eur. J. Immunol. 2009. 39: 1743-1753 DOI 10.1002 Cellular immune response 1743 expressed predominantly by haematopoietic cells, but expression by other cell types can be i...

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Divergent Roles for p55 and p75 Tumor Necrosis Factor Receptors in the Pathogenesis of MOG35-55-Induced Experimental Autoimmune Encephalomyelitis

Cited by 145 publications

References 57 publications

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Cytokines and effector T cell subsets causing autoimmune CNS disease

Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis

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Divergent Roles for p55 and p75 Tumor Necrosis Factor Receptors in the Pathogenesis of MOG35-55-Induced Experimental Autoimmune Encephalomyelitis

Cited by 145 publications

References 57 publications

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Transmembrane TNF-α Promotes Suppressive Activities of Myeloid-Derived Suppressor Cells via TNFR2

Cytokines and effector T cell subsets causing autoimmune CNS disease

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

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Lack of TNFR2 expression by CD4⁺ T cells exacerbates experimental colitis