Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Innate immunity Zhijian J Chen and Sebastian Amigorena Current Opinion in Immunology 2015, 32:v–vi For a complete overview see the Issue Available online 7th February 2015 http://dx.doi.org/10.1016/j.coi.2015.01.016 0952-7915/# 2015 Published by Elsevier Ltd.
Zhijian J Chen
University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected] Zhijian ‘James’ Chen is an Investigator of Howard Hughes Medical Institute, and George L. MacGregor Distinguished Chair in Biomedical Science and Professor in the Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas. Chen discovered the regulatory role of ubiquitination in protein kinase activation in the NF-kB and MAP kinase pathways. In addition, he discovered the Mitochondrial Antiviral Signaling (MAVS) protein that reveals a new role of mitochondria in immunity. More recently, Chen’s laboratory discovered cyclic GMPAMP synthase (cGAS) as a cytosolic DNA sensor and a new cyclic di-nucleotide signaling pathway that mediate innate immune responses in animal cells. His current research is focused on dissecting the signaling mechanisms and physiological functions of the MAVS and cGAS pathways.
Sebastian Amigorena
Cancer and Immunity Unit, Institut Curie, Paris, France e-mail: [email protected] www.sciencedirect.com
Even though innate immunity has been known for over a century to play a critical role in protection against infection, we are still only starting to unravel the immense complexity of cells, molecules and pathways involved in innate protection against infection. Defective innate responses compromise protection against microbes, while its dysregulation can cause severe acute and chronic inflammatory disorders. Innate cells and innate soluble mediators not only interact with each other in different ways, but they also interact with nonhematopoietic cells and tissues, shaping and influencing fundamental physiological process in mammalian organisms. Conservation of the fundamental organization of innate immunity across evolution underscores its critical biological functions from plants to vertebrates. The complexity of innate immunity is currently being approached with a large variety of experimental strategies and tools, at the genetic, biochemical, cellular and physiological levels. One of the main efforts of the community in the last 20 years has been in identifying the mechanisms of innate sensing. After the seminal identification of Toll and Toll-like receptors (TLRs) as the first membrane associated microbial sensors in invertebrates and vertebrates, respectively, a large variety of cytosolic sensors have been identified. Structural analysis of the modes of interaction between microbial conserved molecular patterns and their sensors gives important insights about evolution and functions of innate immunity across species. In this issue, Jean-Luc Imler discusses conservation and diversity, from invertebrates to vertebrates, in the cytosolic sensing of RNA by RIG-I-like receptor and Dicer families. Xin Li gives an overview of biology of the complex family of nucleotide-binding, leucinerich domains receptors (NLRs) in plants, focusing on the signaling pathways involved and the way they recognize pathogens. The reviews by Russell Vance and Feng Shao discuss two different aspects of cytosolic sensing of bacterial products in the cytosol by the inflammasomes. Vance summarizes the structural basis of NAIP/NLRC4 recognition of bacterial ligands and discusses the relevance of this pathway to inflammatory disease in humans. Shao and colleagues discuss a non-canonical sensing pathway of LPS recognition in the cytosol. Biochemical evidence shows that cytosolic sensing of LPS occurs through Caspase-11 in mice and Caspase 4 and 5 in humans; these caspases then trigger anti-bacterial responses and pyroptosis. Nicolas Manel and Takashi Fujita examine two different critical aspects of innate sensing of viral nucleic acids. Fujita focuses on the detection of viral RNA by Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). He discusses how different members of the family recognize different types of viral RNA and trigger specific signaling cascades that restrain viral propagation. Manel reviews the recent advances on understanding how HIV is sensed in different types of immune cells through the detection of the reverse-transcribed retroviral DNA, and more Current Opinion in Immunology 2015, 32:v–vi
vi Innate immunity
Sebastian Amigorena is currently director of the Immunology Department at Institut Curie. His main scientific interests lie at the frontier between immunology and cell biology. He analyzed the functions of IgG receptors and described the molecular basis of their inhibitory properties. He then made several contributions to the understanding of antigen presentation and cross presentation in dendritic cells. His team analyzed dendritic cells’ endocytic pathway and described several unique specializations of their phagocytic pathway, including the regulation of phagosome acidification, antigen export to the cytosol and the interactions of phagosomes with the endoplasmic reticulum. They also used 2-photon intravital microscopy to analyzed cytotoxic T cells dynamics during the initiation of immune responses in lymph nodes, during suppression by Tregs and during T cell the invasion of solid tumors. Amigorena’s current research aims at investigating DC and T cell differentiation, attempting to link cellular functions to chromatin dynamics and epigenetically specified gene expression programs.
specifically how HIV escapes innate sensing and induces AIDS. Along similar lines, Jonathan Kagan discusses the multiple ways in which microbes attempt to escape innate sensing. He reviews the strategies used by viruses and bacteria to antagonize TLR signaling and identifies a series of potential mode of interference for future research. Rodolphe Barrangou describes the recently discovered CRISP-Cas system as an immune defense mechanism in bacteria and archaea. He discusses the possible relevance of this system to other biological functions beyond innate immunity. The review by Philippe Pierre discusses regulation of protein translation as an effector innate mechanism. He summarizes current knowledge about how the sensing of cellular stress and metabolism controls mRNA translation. Gordon D Brown dives a wide overview about c-type lectin structure and functions, discussing their role not only in different aspects of host defense, but also in autoimmunity and allergy. Shannon Turley provides an insightful discussion about the role of stromal cells in immune tolerance, focusing on the liver. Stromal cells play critical roles in maintaining immunological tolerance through a variety of mechanisms, ranging from the induction of regulatory T cells to suppressive myeloid cells. The review by Caetano Reis e Sousa further discusses another critical cell type involved in maintaining immunological homeostasis, dendritic cells. This review discusses the central issue of defining dendritic cells as a bona fide cell lineage and proposes an ‘ontogeny-based’ view of the issue, based on recent advances in understanding dendritic cell differentiation pathways. Marco Colonna gives us an updated overview of innate lymphocyte ontogeny, subsets and functions, discussing in particular the interactions of innate lymphocytes with the microbiota and other hematopoietic cells. Two reviews discuss how human genetics made critical contributions to understanding innate immune responses in recent years. Jean-Laurent Casanova describes how primary human immunodeficiencies affect immunity in humans, providing invaluable insights into the role of particular innate pathways in protection against particular microbes. He focuses on a growing family of primary immunodeficiencies caused by dominant gain of function mutations that affect critical players of the innate immune system. Yanick Crow discusses a very interesting and important category of autoimmune and autoinflammatory diseases, termed type I interferonopathies, which are characterized by elevated levels of interferon-induced genes (ISGs). He illustrates how studies of these patients helped understand the innate immune pathways such as the cytosolic nucleic acid sensing pathways, and how basic research in these pathways helped explain the human diseases. Finally, a review by Vassili Soumelis proposes a systems biology approach to understanding innate immunity. He summarizes current strategies to understand the functional diversity of cells and pathways of immunity, and proposes a conceptual framework to study signal integration and cell-to-cell communication systematically. We hope that this series of reviews will help the reader understand how the innate immune system functions from plants to humans, what are the key molecules and pathways involved in innate protection against infection and what are the major experimental approaches and biological systems use to analyze them. These and many other studies on innate immunity have already resulted in major recent therapeutic advances in the treatment of inflammatory diseases. Further understanding of the fundamental mechanisms of innate immune responses will undoubtedly promote the rational design of new approaches and drugs for the treatment of other diseases, including cancer.
Current Opinion in Immunology 2015, 32:v–vi
www.sciencedirect.com
ScienceDirect Editorial overview: Innate immunity Zhijian J Chen and Sebastian Amigorena Current Opinion in Immunology 2015, 32:v–vi For a complete overview see the Issue Available online 7th February 2015 http://dx.doi.org/10.1016/j.coi.2015.01.016 0952-7915/# 2015 Published by Elsevier Ltd.
Zhijian J Chen
University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected] Zhijian ‘James’ Chen is an Investigator of Howard Hughes Medical Institute, and George L. MacGregor Distinguished Chair in Biomedical Science and Professor in the Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas. Chen discovered the regulatory role of ubiquitination in protein kinase activation in the NF-kB and MAP kinase pathways. In addition, he discovered the Mitochondrial Antiviral Signaling (MAVS) protein that reveals a new role of mitochondria in immunity. More recently, Chen’s laboratory discovered cyclic GMPAMP synthase (cGAS) as a cytosolic DNA sensor and a new cyclic di-nucleotide signaling pathway that mediate innate immune responses in animal cells. His current research is focused on dissecting the signaling mechanisms and physiological functions of the MAVS and cGAS pathways.
Sebastian Amigorena
Cancer and Immunity Unit, Institut Curie, Paris, France e-mail: [email protected] www.sciencedirect.com
Even though innate immunity has been known for over a century to play a critical role in protection against infection, we are still only starting to unravel the immense complexity of cells, molecules and pathways involved in innate protection against infection. Defective innate responses compromise protection against microbes, while its dysregulation can cause severe acute and chronic inflammatory disorders. Innate cells and innate soluble mediators not only interact with each other in different ways, but they also interact with nonhematopoietic cells and tissues, shaping and influencing fundamental physiological process in mammalian organisms. Conservation of the fundamental organization of innate immunity across evolution underscores its critical biological functions from plants to vertebrates. The complexity of innate immunity is currently being approached with a large variety of experimental strategies and tools, at the genetic, biochemical, cellular and physiological levels. One of the main efforts of the community in the last 20 years has been in identifying the mechanisms of innate sensing. After the seminal identification of Toll and Toll-like receptors (TLRs) as the first membrane associated microbial sensors in invertebrates and vertebrates, respectively, a large variety of cytosolic sensors have been identified. Structural analysis of the modes of interaction between microbial conserved molecular patterns and their sensors gives important insights about evolution and functions of innate immunity across species. In this issue, Jean-Luc Imler discusses conservation and diversity, from invertebrates to vertebrates, in the cytosolic sensing of RNA by RIG-I-like receptor and Dicer families. Xin Li gives an overview of biology of the complex family of nucleotide-binding, leucinerich domains receptors (NLRs) in plants, focusing on the signaling pathways involved and the way they recognize pathogens. The reviews by Russell Vance and Feng Shao discuss two different aspects of cytosolic sensing of bacterial products in the cytosol by the inflammasomes. Vance summarizes the structural basis of NAIP/NLRC4 recognition of bacterial ligands and discusses the relevance of this pathway to inflammatory disease in humans. Shao and colleagues discuss a non-canonical sensing pathway of LPS recognition in the cytosol. Biochemical evidence shows that cytosolic sensing of LPS occurs through Caspase-11 in mice and Caspase 4 and 5 in humans; these caspases then trigger anti-bacterial responses and pyroptosis. Nicolas Manel and Takashi Fujita examine two different critical aspects of innate sensing of viral nucleic acids. Fujita focuses on the detection of viral RNA by Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). He discusses how different members of the family recognize different types of viral RNA and trigger specific signaling cascades that restrain viral propagation. Manel reviews the recent advances on understanding how HIV is sensed in different types of immune cells through the detection of the reverse-transcribed retroviral DNA, and more Current Opinion in Immunology 2015, 32:v–vi
vi Innate immunity
Sebastian Amigorena is currently director of the Immunology Department at Institut Curie. His main scientific interests lie at the frontier between immunology and cell biology. He analyzed the functions of IgG receptors and described the molecular basis of their inhibitory properties. He then made several contributions to the understanding of antigen presentation and cross presentation in dendritic cells. His team analyzed dendritic cells’ endocytic pathway and described several unique specializations of their phagocytic pathway, including the regulation of phagosome acidification, antigen export to the cytosol and the interactions of phagosomes with the endoplasmic reticulum. They also used 2-photon intravital microscopy to analyzed cytotoxic T cells dynamics during the initiation of immune responses in lymph nodes, during suppression by Tregs and during T cell the invasion of solid tumors. Amigorena’s current research aims at investigating DC and T cell differentiation, attempting to link cellular functions to chromatin dynamics and epigenetically specified gene expression programs.
specifically how HIV escapes innate sensing and induces AIDS. Along similar lines, Jonathan Kagan discusses the multiple ways in which microbes attempt to escape innate sensing. He reviews the strategies used by viruses and bacteria to antagonize TLR signaling and identifies a series of potential mode of interference for future research. Rodolphe Barrangou describes the recently discovered CRISP-Cas system as an immune defense mechanism in bacteria and archaea. He discusses the possible relevance of this system to other biological functions beyond innate immunity. The review by Philippe Pierre discusses regulation of protein translation as an effector innate mechanism. He summarizes current knowledge about how the sensing of cellular stress and metabolism controls mRNA translation. Gordon D Brown dives a wide overview about c-type lectin structure and functions, discussing their role not only in different aspects of host defense, but also in autoimmunity and allergy. Shannon Turley provides an insightful discussion about the role of stromal cells in immune tolerance, focusing on the liver. Stromal cells play critical roles in maintaining immunological tolerance through a variety of mechanisms, ranging from the induction of regulatory T cells to suppressive myeloid cells. The review by Caetano Reis e Sousa further discusses another critical cell type involved in maintaining immunological homeostasis, dendritic cells. This review discusses the central issue of defining dendritic cells as a bona fide cell lineage and proposes an ‘ontogeny-based’ view of the issue, based on recent advances in understanding dendritic cell differentiation pathways. Marco Colonna gives us an updated overview of innate lymphocyte ontogeny, subsets and functions, discussing in particular the interactions of innate lymphocytes with the microbiota and other hematopoietic cells. Two reviews discuss how human genetics made critical contributions to understanding innate immune responses in recent years. Jean-Laurent Casanova describes how primary human immunodeficiencies affect immunity in humans, providing invaluable insights into the role of particular innate pathways in protection against particular microbes. He focuses on a growing family of primary immunodeficiencies caused by dominant gain of function mutations that affect critical players of the innate immune system. Yanick Crow discusses a very interesting and important category of autoimmune and autoinflammatory diseases, termed type I interferonopathies, which are characterized by elevated levels of interferon-induced genes (ISGs). He illustrates how studies of these patients helped understand the innate immune pathways such as the cytosolic nucleic acid sensing pathways, and how basic research in these pathways helped explain the human diseases. Finally, a review by Vassili Soumelis proposes a systems biology approach to understanding innate immunity. He summarizes current strategies to understand the functional diversity of cells and pathways of immunity, and proposes a conceptual framework to study signal integration and cell-to-cell communication systematically. We hope that this series of reviews will help the reader understand how the innate immune system functions from plants to humans, what are the key molecules and pathways involved in innate protection against infection and what are the major experimental approaches and biological systems use to analyze them. These and many other studies on innate immunity have already resulted in major recent therapeutic advances in the treatment of inflammatory diseases. Further understanding of the fundamental mechanisms of innate immune responses will undoubtedly promote the rational design of new approaches and drugs for the treatment of other diseases, including cancer.
Current Opinion in Immunology 2015, 32:v–vi
www.sciencedirect.com
