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Immune signalling in health and disease

Plenary lecture 3

Tuesday, 13 September, 13:30 - 15:00

Room: Musensaal (Saal 2.0)

Ronald N. Germain US

NIH, Bethesda

Imaging Immunity: Developing a Spatiotemporal Understanding of Host Defense and Disease
Background: Immune responses involve cell-cell interactions within lymphoid tissues, together with trafficking and migration of effector cells to and within peripheral tissues. To gain insight into the relationships among cell movement, tissue architecture, and immune function, we have used intravital multiphoton microscopy and a novel multiplex immunohistochemical method called Histo-cytometry.Observations: Migrating T cells follow stromal pathways in lymph nodes, with chemokine cues facilitating interactions among rare antigen-presenting and antigen-recognizing cells. In tissue sites, effector cells stop when they perceive antigen and undergo transient activation and cytokine release, then tune their response to existing antigen levels. The role of cell localization in immunity has also been addressed using Histo-cytometry. With an ability to use as many as 14 different colors and antibodies to surface markers, phospho-proteins and cytokines, and 2D and 3D analyses, our multiplex imaging technology facilitates analysis of the phenotype, number, location, signaling state, and function of immune cells and stromal elements in infected, inflamed, or tumor sites. Conclusion: This talk will illustrate the power of in situ imaging for probing the molecular, cellular, spatial, and temporal aspects of cell function and signaling events in host immune responses. (Supported in part by the Intramural Research Program of the NIH, NIAID. Germain, RN1, Laemmermann, T,2, Uderhardt, S, , Liu, Z, Rudensky, AY3,4, Levine, AG3,4, Li, W, Radtke, A, Yu, W, Pires da silva Baptista, A, Gerner,MY.1,51Laboratory of Systems Biology, NIAID, NIH, Bethesda, MD USA 20892; 2Present address: Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; 3HHMI, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 4Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA;5 Present address: Dept. of Immunology, Univ. of Washington, Seattle, WA.)

 
Biography
Ronald N. Germain received his M.D. and Ph.D. in 1976 from Harvard University, the latter for research with B. Benacerraf, recipient of the 1980 Nobel Prize in Physiology and Medicine. Since that time, he has investigated basic  immunobiology, first on the faculty of Harvard Medical School, from 1982-2011 as the Chief, Lymphocyte Biology Section, Laboratory of Immunology, NIAID, NIH, and from 2011 as Chief, Laboratory of Systems Biology, NIAID, NIH. Over the years, his research group has made key contributions to understanding Major Histocompatibility Complex (MHC) class II molecule structure–function relationships, the cell biology of antigen processing, and the molecular basis of T cell recognition. More recently, the laboratory has been focused on the details of T cell-antigen presenting cell interactions and the relationship between immune tissue organization and control of adaptive and innate immunity. Experiments at the whole cell, tissue, and organism level have been used to build a more complete picture of the operation of the adaptive immune system, including those utilizing novel dynamic and multiplex static imaging methods that his laboratory helped pioneer. Efforts are also underway to create computer models of T cell and TLR signaling based on these studies. The aim of this work is to create a detailed understanding of how the immune system operates and to develop new tools for prediction of how the immune system will respond if perturbed, for example, by a candidate vaccine by creating and applying the next generation of computer software and research tools for quantitative modeling and simulation of complex biological systems. He has published more than 300 scholarly research papers and reviews. Among numerous honors, he was elected as an Associate member of EMBO (2008), a member of the IOM, NAS (2013), an honorary member of the Scandinavian Society for Immunology (2011), awarded the Landsteiner Medal of the Austrian Society for Allerology and Immunology (2008), chosen as an NIH Distinguished Investigator (2011), awarded the American Association of Immunologists Meritorious Career Award (2015), and invited to present numerous named lectureships at major academic institutions in the US and abroad. He serves as an associate or advisory editor of the J Exp Med, Immunity, Current Biology, Mol Systems Biol, BMC Biology, Nature Communications, eLife, and Int Immunol, and have previously served as Deputy Editor of J Immunol and Editor, Immunity. He helped co-found the Immunology Interest Group and Systems Biology Interest Group at NIH and currently serve as Associate Director for the trans-NIH Center for Human Immunology.  The Lymphocyte Biology Section he leads has trained dozens of postdoctoral fellows, many of whom now occupy senior academic posts and are internationally recognized investigators.

 

Jannie Borst NL

Netherlands Cancer Institute (NKI), Amsterdam

How CD4 T cells help the cytotoxic CD8 T cell response: the molecular basis
T cell activation takes place in secondary lymphoid organs, when T cells interact with antigen-presenting dendritic cells (DC). An exchange of information with the DC leads to T-cell proliferation and acquisition of effector and memory functions. CD4 T cells can “help” to optimize the CD8 T-cell response, which is very important for therapeutic vaccine design. Intravital microscopy and immunofluorescent imaging has recently visualized the scenario wherein CD4 T-cell “help” is delivered: a CD4 T cell and a CD8 T cell interact simultaneously with the same DC that relays the signal. Which signals are transferred from the CD4 T cell to the DC and subsequently from the DC to the CD8 T cell is largely unknown. We have created a vaccination setting in mice that optimally reveals the consequences of CD4 T-cell help for the cytotoxic T cell (CTL) response in terms of antigen-specific CD8 T-cell expansion, effector and memory differentiation (Ahrends T, et al. Cancer Res. 2016). The robustness of this model has allowed us to identify the molecular basis of CD4 T-cell help for the CTL response, by ex vivo transcriptomics in CD8 T cells and functional validation. We have identified multiple molecular mechanisms that optimize CD8 T-cell function, which can be exploited for diagnostics and targeted (cancer) immunotherapy.

Biography

Jannie Borst obtained a Master in Biology with Chemistry at Leiden University in 1980. She did the major part of her PhD work at the Dana-Farber Cancer Institute, Harvard Medical School in Boston, under supervision of biochemist prof. Cox P. Terhorst. She came back to The Netherlands to work with immunologists dr. Jan E. de Vries and dr. Hergen Spits and obtained her Ph.D. degree from Leiden University in 1985. In 1987, she started her independent career with the aid of a 5-year personal fellowship from The Netherlands Organization for Scientific Research. In 1992, she obtained a staff scientist position at the NKI-AVL and in 2002 she became the head of the Division of Immunology. In 1999, she was appointed professor in Experimental Oncology at the University of Amsterdam. In 2009, she was presented with the Van Loghem career award of the Dutch Society of Immunology and in 2012, she was elected EMBO member.

Francisco Sánchez-Madrid ES

Hospital de la Princesa, Madrid

The role of the leukocyte activation receptor in the immune Inflammatory response: its ligands and associated molecules
The early activation antigen CD69 is involved in immune cell homeostasis, regulating Th17 and Treg cells differentiation. Multiple different models of chronic inflammation support the role of CD69 as an immune-regulatory molecule. However, the identification of natural ligands for CD69 has remained elusive until very recently. The description of Galectin-1 as a dendritic cell ligand for CD69 has confirmed the regulatory action of this molecule on Th17 differentiation in both mice and human. Beside Galectin-1, we have recently identified the association of CD69 with the amino acid transport LAT1/CD98 and its interaction with oxidized lipoproteins. Upon CD69 interaction with oxidized lipoproteins there is an induction of transcription factors involved in Tregs differentiation. The influence of CD69 binding to lipoproteins has been evaluated in vivo in a model of atherosclerosis. This model has allowed identifying CD69 as a functional lymphocyte receptor for lipoproteins that contributes to the regulation of initial atheroma plaque formation through the control of Treg/Th17 immune balance.   In addition, the development of Psoriasis in CD69 deficient mice highlights the influence of this molecule in the development and progression of skin inflammation. The CD69 expression controls the uptake of amino acids regulating Aryl Hydrocarbon Receptor activation and IL-22 secretion in Gamma-Delta T cells, a key proinflammatory cytokine in the pathogenesis of Psoriasis. These novel interactions of CD69 greatly contribute to the better understanding of CD69 in the regulation of the immune response.

Biography

Francisco Sánchez-Madrid did his postdoctoral training at Harvard Medical School, Boston, Massachusetts, USA. He is Professor of Immunology at the Universidad Autónoma de Madrid, Spain, Chief of Service of Immunology and the Scientific Director of the Hospital Princesa Research Institute, Madrid, Spain. He has made leading contributions to knowledge about the mechanisms of leukocyte adhesion, polarity, migration and activation. This contribution has pioneered the identification and characterization of the first families of leukocyte adhesion molecules, their physiological role in the control of migration and cellular traffic and their immense relevance to chronic inflammatory pathologies. His laboratory research on migration and activation receptors of human leukocytes is documented in more than 390 publications in international journals, including many recent articles in prestigious journals that have to date received more than 24.500 citations. In the most recent years, his research group has made key contributions to understanding the functional relevance of the supra-molecular organization of leukocyte and endotelial nanoplatforms connected to cytoskeleton in the regulation of cell-to-cell communication in the immune system and the mechanisms of transfer of genetic information by exosomes.