Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling

The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

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Negative feedback contributes to the stochastic expression of the interferon-β gene in virus-triggered type I interferon signaling pathways

Mathematical Biosciences ◽

10.1016/j.mbs.2015.04.003 ◽

2015 ◽

Vol 265 ◽

pp. 12-27 ◽

Cited By ~ 6

Author(s):

Wei Zhang ◽

Tianhai Tian ◽

Xiufen Zou

Keyword(s):

Signaling Pathways ◽

Negative Feedback ◽

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Interferon Β ◽

Stochastic Expression

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The molecular basis for functional plasticity in type I interferon signaling

Trends in Immunology ◽

10.1016/j.it.2015.01.002 ◽

2015 ◽

Vol 36 (3) ◽

pp. 139-149 ◽

Cited By ~ 103

Author(s):

Gideon Schreiber ◽

Jacob Piehler

Keyword(s):

Molecular Basis ◽

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Functional Plasticity

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Faculty Opinions recommendation of Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1165559.628567 ◽

2009 ◽

Author(s):

E Charles Snow

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

T Follicular Helper Cells ◽

Helper Cells ◽

Follicular Helper

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Faculty Opinions recommendation of Blockade of chronic type I interferon signaling to control persistent LCMV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717999659.793474946 ◽

2013 ◽

Author(s):

Giorgio Trinchieri

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Chronic Type ◽

Lcmv Infection

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Faculty Opinions recommendation of Persistent LCMV infection is controlled by blockade of type I interferon signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717999658.793476087 ◽

2013 ◽

Author(s):

Alan Landay

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Lcmv Infection

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Faculty Opinions recommendation of USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718217888.793499915 ◽

2014 ◽

Author(s):

Ganes Sen ◽

Saurabh Chattopadhyay

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling

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Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

Journal of Virology ◽

10.1128/jvi.01099-18 ◽

2018 ◽

Vol 92 (23) ◽

Cited By ~ 1

Author(s):

Keigo Kawashima ◽

Masanori Isogawa ◽

Susumu Hamada-Tsutsumi ◽

Ian Baudi ◽

Satoru Saito ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Type I Interferon ◽

T Cell Responses ◽

Antigen Expression ◽

Type I ◽

Interferon Signaling ◽

Cell Responses ◽

B Virus

ABSTRACT Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR–/–) (H-2b) mice. The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels. IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

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Lung Epithelial Regulation of BCL2 Related Protein A1 (BCL2A1) by Coronaviruses (SARS-CoV) and Type I Interferon Signaling

10.1101/2021.07.21.453244 ◽

2021 ◽

Author(s):

Ramana Chilakamarti

Keyword(s):

Epithelial Cells ◽

Human Lung ◽

Type I Interferon ◽

Respiratory Viruses ◽

Lung Epithelial Cells ◽

Type I ◽

Related Protein ◽

Interferon Signaling ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

Highly pathogenic respiratory viruses such as 1918 influenza (HIN1) and coronavirus (SARS-CoV-2) induce significant lung injury with diffuse alveolar damage, capillary leak, and extensive cell death resulting in acute respiratory distress syndrome (ARDS). Direct effects of the virus, as well as host immune response such as proinflammatory cytokine production, contribute to programmed cell death or apoptosis. Alveolar lung epithelial type II (AT2) cells play a major role in the clearance of respiratory viruses, secretion of surfactant proteins and antimicrobial substances into the bronchoalveolar fluid as well as repair of lung injury. Gene expression in AT2 cells is regulated in a tissue and cell-specific manner and in a temporal fashion. The availability of tissue and cell-specific RNA datasets in Human Protein Atlas led to the identification of localized expression patterns of BCL-2 family members such as BCL2 related protein A1 (BCL2A1) in AT2 cells and immune cells of the lung. BCL2A1 expression was regulated by multiple stimuli including Toll-like receptor (TLR) ligands, interferons (IFNs), inflammatory cytokines, and inhibited by the steroid dexamethasone. In this study, regulation of BCL2A1 gene expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. SARS-CoV-2 infection significantly induced BCL2A1 expression in human lung epithelial cells within 24 hours that required the expression of Angiotensin-converting enzyme 2 (ACE2). BCL2A1 mRNA induction by SARS-CoV-2 was correlated with the induced expression of IFN-β and IFN-regulated transcription factor mRNA. BCL2A1 was induced by IFN-β treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE cells. Furthermore, bioinformatics revealed that a subset of BCL-2 family members involved in the control of apoptosis and transcription such as BCL2A1, BCL2L14, BCL3, and BCL6 were regulated in the lung epithelial cells by coronaviruses and in the lung tissue samples of COVID-19 patients. Transcriptomic data also suggested that these genes were differentially regulated by the steroid drug dexamethasone.

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