The role of protein kinase C-theta in T cell activation, survival and homeostasis.

The role of protein kinase C-theta in T cell activation, survival and homeostasis

Modulation of Inflammatory Responses by Wnt/β-catenin Signaling in Dendritic cells: A Novel Immunotherapy target for auto-immunity and Cancer

The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic auto-immune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade anti-tumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β -catenin pathway can be targeted for successful therapeutic interventions in various human diseases

The p150 Isoform of ADAR1 Blocks Sustained RLR signaling and Apoptosis during Influenza Virus Infection

Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.</p

RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection

Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 –MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains

Analysis of in vivo dynamics of influenza virus infection using a GFP reporter virus.

Influenza A virus Is being extensively studied due to its major Impact in human and animal health. However, the dynamics of Influenza virus Infection and the cell types infected In vivo are poorly understood. These characteristics are not easy to determine parUy because currently there Is no replication-competent virus expressing a fluorescent reporter gene. Here, we report the generation of a complete Influenza virus carrying a GFP reporter gene In the NS segment of its genome (NS1-GFP virus). NS1-GFP virus replicates efficiently in cell culture and shows pathogenicity In mice at levels similar to parental virus. We have analyzed the In vivo dynamics of influenza Infection progression in mice by flow cytometry and whole organ Imaging of infected lungs. Using flow cytometric analysis of infected lungs, apart from epithelial cells, we find antigen presenting cells like CD11c+, CD11b+ CD11c+, CD11b+ and B cells to be GFP positive. In addition, NK cells are susceptible to Influenza Infection. Whole organ imaging of lungs show that influenza infection starts In the respiratory tract In areas closer to large conducting airways and with time spreads to deeper sections of the lungs. We have also tested the effects of oseltamivir and amantadine on the kinetics and In vivo infection progression in mice and find Interesting differences In the effects of these antivirals. Treatment with oseltamlvlr dramatically reduces Influenza Infection in all cell types, whereas, Interestingly, amantadine treatment blocks infection In a cell type specific manner

RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection

Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 -MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains