Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses

Gorby, Claire; Bellón, Junel Sotolongo; Wilmes, Stephan; Warda, Walid; Pöhler, Elizabeth; Fyfe, Paul K.; Cozzani, Adeline; Ferrand, Christophe; Walter, Mark R.; Mitra, Suman; Piehler, Jacob; Moraga, Ignacio

doi:10.1126/scisignal.abc0653

Cited by 54 publications

(52 citation statements)

References 68 publications

(101 reference statements)

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“…2b), albeit exhibiting similar pSTAT1 amplitudes for IL-27 and HypIL-6, most likely because of the high endogenous levels of GP130 in RPE1 cells. We used previously described RPE1 GP130 KO cells (Figure 1-figure supplement 2) (35) to transfect and express tagged variants of IL-27R and GP130, to allow quantitative site-specific fluorescence cell surface labelling by dye-conjugated nanobodies (NBs) (Figure 1e) as recently described in (36). For both IL-27R and GP130 we found a random distribution and unhindered lateral diffusion of individual receptor monomers (Figure 1f).…”

Section: Ligand-induced Cell-surface Receptor Assembly By Il-27 and Hypil-6mentioning

confidence: 80%

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Wilmes

Jeffrey

Martínez-Fábregas

et al. 2021

eLife

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Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

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Section: Ligand-induced Cell-surface Receptor Assembly By Il-27 and Hypil-6mentioning

confidence: 80%

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Wilmes

Jeffrey

Martínez-Fábregas

et al. 2021

eLife

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“…Fig. 2a) ( 34 ) to transfect and express tagged variants of IL-27Rα and GP130, to allow quantitative site-specific fluorescence cell surface labelling by dye-conjugated nanobodies (NBs) (Figure 1e) as recently described in ( 35 ). For both IL-27Rα and GP130 we found a random distribution and unhindered lateral diffusion of individual receptor monomers (Figure 1f).…”

Section: Resultsmentioning

confidence: 99%

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Wilmes

Jeffrey

Martínez-Fábregas

et al. 2021

Preprint

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Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with Systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

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“…The combination of IL-10 and IL-2 supports CD8 T cell effector function. Specifically, CD8 T cells activated in vitro in the presence of the IL-10/IL-2 combination increase expression of granzyme B and downregulate genes associated with T cell exhaustion (68). In vitro activation with supplemental IL-10 alone has been shown to increase expression of granzymes and IFN-g (69).…”

Section: Discussionmentioning

confidence: 99%

Control of B Cell Lymphoma by Gammaherpesvirus-Induced Memory CD8 T Cells

Preiss

Kang

Usherwood

et al. 2020

The Journal of Immunology

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Persistent infection with gammaherpesviruses (gHV) can cause lymphomagenesis in immunocompromised patients. Murine gHV-68 (MHV-68) is an important tool for understanding immune factors contributing to gHV control; however, modeling control of gHV-associated lymphomagenesis has been challenging. Current model systems require very long incubation times or severe immune suppression, and tumor penetrance is low. In this report, we describe the generation of a B cell lymphoma on the C57BL/ 6 background, which is driven by the Myc oncogene and expresses an immunodominant CD8 T cell epitope from MHV-68. We determined MHV-68-specific CD8 T cells in latently infected mice use either IFN-g or perforin/granzyme to control gHVassociated lymphoma, but perforin/granzyme is a more potent effector mechanism for lymphoma control than IFN-g. Consistent with previous reports, CD4-depleted mice lost control of virus replication in persistently infected mice. However, control of lymphoma remained intact in the absence of CD4 T cells. Collectively, these data show the mechanisms of T cell control of B cell lymphoma in gHV-infected mice overlap with those necessary for control of virus replication, but there are also important differences. This study establishes a tool for further dissecting immune surveillance against, and optimizing adoptive T cell therapies for, gHV-associated lymphomas.

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Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses

Cited by 54 publications

References 68 publications

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Control of B Cell Lymphoma by Gammaherpesvirus-Induced Memory CD8 T Cells

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