Ronald N. Germain, M.D., Ph. D.
NIAID Scientists Describe How Immune System Overreaction Contributes to Influenza Deaths
Chief, Laboratory of Systems BiologyChief, Lymphocyte Biology Section, LSB
The Lymphocyte Biology Section (LBS) studies basic aspects of innate and adaptive immune function, with an emphasis on the discrimination between self and foreign peptide-associated MHC molecules by T-cells as well as on T-cell antigen-presenting cell interactions and the subsequent delivery of effector function. Experiments at the biochemical, cell, tissue, and organism levels are used to build a more complete picture of both the operation of and the interface between the adaptive and innate immune systems, including the use of novel microscopic live animal imaging methods and a new technique for highly multiplex analysis of cell phenotype, signaling state, and function in complex tissue environments. Efforts are also underway to create computer models of immune function, both at the tissue and single cell level, with a current emphasis on TLR signaling pathways. Collaborative work is also underway to use systems methods to analyze the human immune response. The aim of this work is to create a detailed understanding of how immune responses to foreign pathogens or self antigens are initiated and unfold, as well as to develop new tools for predicting how the immune system will respond if perturbed, for example, by a candidate vaccine.
For more insight into the research of LBS and Dr. Germain, read “Ron Germain: Towards a grand unified theory,” an interview that appears in the February 15, 2010, issue of the Journal of Experimental Medicine.
Imaging Immune Cell Dynamics and Function
LBS has made numerous contributions to the understanding of the cell biology of antigen processing and presentation by MHC class I and especially class II molecules. It also pioneered development of monoclonal antibodies to specific peptide-MHC molecule complexes and their use for visualization of the antigen presentation.
We have now moved from these studies of MHC-peptide ligand formation to studies of the recognition of these ligands by T cells. An exciting development is the establishment of multiphoton microscopy methods for real-time, high-resolution visualization of immune-cell dynamics in situ. This new technology is being used in conjunction with more conventional molecular and cellular immunological methods to: 1) describe the dynamics of innate and adaptive immune cell movement in lymphoid and non-lymphoid tissue environments and to uncover the underlying mechanisms driving and guiding this cell movement; 2) localize the sites and duration of the cell-cell interactions involved in the development of adaptive immune responses; 3) analyze how differences in these aspects of cell migration and interaction affect differentiation events and functional immunity; and 4) investigate the dynamic behavior and effector activities of innate and adaptive immune cells in non-lymphoid sites, especially in the context of infections with various microbial and parasitic agents.
Our studies have allowed us to determine how long a T cell spends in contact with an antigen-bearing dendritic cell, the role of both physical (the fibroblastic reticular cell network in lymph nodes) and chemical (chemokine) cues in controlling T-cell migration in secondary lymphoid tissues, the contribution of dendritic cell-associated antigens to the activation of naïve B cells in vivo, the importance of SAP in differential attachment of T cells to antigen-presenting dendritic cells versus B cells and in germinal center formation, the involvement of neutrophils in Leishmania infection of the skin, epithelial cell TLR control of dendritic-cell extension into the gut lumen for bacterial sampling, and the interplay of myeloid and lymphoid cells within mycobacterial granulomas in the liver. Videos from published papers reporting these findings are available in the Videos tab.
Together, these studies are beginning to create a comprehensive picture of how immune cells traffic and interact during the earliest stages of immune responses, during the initiation of adaptive immunity, and during the delivery of effector functions in peripheral tissues.
Analysis and Modeling of T Cell Ligand Discrimination and Activation Control
A second major focus of LBS is on how antigen-receptor binding events are translated into intracellular signals regulating T-cell activation and differentiation. Previous contributions include an early description of TCR antagonists and partial agonists, the discovery that such ligands induce distinct early tyrosine phosphorylation events, and the recognition that the "wiring" connecting ligand engagement of the TCR to gene activation was modified during development to support effective positive and negative selection.
Ongoing work centers on dissecting the molecular basis for antigen discrimination and developmental changes in receptor-response linkage. We have identified two novel feedback regulatory pathways that help the T cell discriminate functionally between ligands of closely related structure. Such selectivity is at the heart of physiologic self/non-self discrimination. We have also uncovered evidence for a very important role of self-recognition in responses to foreign antigen that help explain the contribution of thymic-positive selection to adaptive immunity. These data are now being expanded by identification and analysis of additional TCR-linked feedback regulatory pathways involved in the control of T-cell activation and effector responses, as well as by the development of integrated computational models of early ligand discrimination by the TCR and downstream feedback control of intracellular signaling pathways. These mechanistic studies complement higher-order imaging studies in the development of a multiscale understanding of immune function. See all videos from LBS Research.
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Dr. Germain received his Sc.B. and Sc.M. from Brown University in 1970 and his M.D. and Ph.D. from Harvard Medical School and Harvard University in 1976. From 1976 to 1982, he served as an instructor, assistant professor, and associate professor of pathology at Harvard Medical School. From 1982 to 1987, he worked as a senior investigator in the Laboratory of Immunology (LI). In 1987, he was appointed chief of the Lymphocyte Biology Section. In 1994, Dr. Germain was named deputy chief of LI. In 2006, he became director of the NIAID Program in Systems Immunology and Infectious Disease Modeling, which became the Laboratory of Systems Biology in 2011.
Egen JG, Rothfuchs AG, Feng CG, Horwitz MA, Sher A, Germain RN. Intravital imaging reveals limited antigen presentation and T-cell effector function in mycobacterial granulomas. Immunity. 2011 May 27;34(5):807-19.
Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011 Apr 23;29:527-85.
Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature.2008 Oct 9;455(7214):764-9.
Feinerman O, Veiga J, Dorfman JR, Germain RN, Altan-Bonnet G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science. 2008 Aug 22;321(5892):1081-4.
Bajénoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006 Dec;25(6):989-1001.
Castellino F, Huang AYC, Altan–Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic interaction. Nature. 2006 Apr 13;440(7086):890-5.
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Last Updated June 18, 2014