Mutational switch of an IL-6 response to an interferon-γ-like response

Costa-Pereira, Ana P.; Tininini, Silvia; Strobl, Birgit; Alonzi, Tonino; Schlaak, Joerg F.; Is'harc, Hayaatun; Gesualdo, Ida; Newman, Sally J.; Kerr, Ian M.; Poli, Valeria

doi:10.1073/pnas.122236099

Cited by 245 publications

(238 citation statements)

References 28 publications

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“…STAT3 activation is enhanced in STAT1-null cells, and conversely, STAT1 activation is enhanced in STAT3-null cells. 16,[60][61][62][63] Although our studies did not show a difference in STAT3 phosphorylation during re-stimulation in a Tc1 environment, STAT1 phosphorylation was significantly altered. As STAT3 and STAT1 have different functions and even oppose each other, their ratio determines the Tc17 cell phenotype.…”

Section: Discussioncontrasting

confidence: 76%

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8 C T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8 C T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORgt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNg and TNF-a co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.

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Section: Discussioncontrasting

confidence: 76%

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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“…Specifically TNF␣ has been shown to up-regulate PLAA and CASP6 (51,52), both of which increased after IR in the wild type but not in the mutant. Decreased TNF␣ activity in p53 K317R thymocytes is also consistent with the observed lack of change in WARS, TCF7, and ETFDH protein levels after IR; all of these proteins are indirectly regulated by TNF␣ (53)(54)(55)(56)(57)(58). Finally TNF␣ has been shown to induce the expression of TGF␤1 (59), which has been shown to increase the expression of FABP5 and SSRP1 (60,61), two additional proteins that exhibit the same pattern.…”

Section: Discussionsupporting

confidence: 73%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes posttranslationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53 K317R knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53 K317R thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53 K317R samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53 K317R mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R thymocytes as well as a decrease in tumor necrosis factor ␣ signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between

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“…By comparison, another stereotypical STAT signaling pathway is the STAT1-mediated IFN response. Like the AIR, the STAT1-mediated IFN response can be generated from receptors other than the IFN receptors by manipulating levels of key signaling components (20,31,40). The findings we reported have implications for understanding the AIR in cells other than IL-10-responsive macrophages.…”

Section: Discussionmentioning

confidence: 78%

General Nature of the STAT3-Activated Anti-Inflammatory Response

Kasmi

Holst²,

Coffre

et al. 2006

The Journal of Immunology

201

179

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Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.

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Mutational switch of an IL-6 response to an interferon-γ-like response

Cited by 245 publications

References 28 publications

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

General Nature of the STAT3-Activated Anti-Inflammatory Response

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