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Ronald N. Germain, M.D., Ph. D.
Building 4, Room 126A
4 Memorial Drive
Bethesda, MD 20892-0421​
Phone: 301-496-1904
Fax: 301-480-1660
rgermain@niaid.nih.gov

Center for Human Immunology, Autoimmunity, and Inflammation (CHI)

Laboratory of Systems Biology

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Ronald N. Germain, M.D., Ph.D.

Photo of Ronald N. Germain

Chief, Laboratory of Systems Biology
Chief, Lymphocyte Biology Section, LSB

Major Areas of Research

  • Intravital imaging, analysis, and modeling of immune cell dynamics and in vivo activity
  • Control of cell migration and cell-cell interactions by structural and chemical cues
  • Multiplex imaging of cell phenotype, signaling, and function in complex tissues
  • Systems-level analysis of immune cell signaling and responses to infection
  • Human immune analysis using systems biology methods
 

Program Description

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

 

combination photo of a Polarized T cell, polyclonal B cells, dendritic cells, and activated T cells
From L to R: Polarized T cell (cyan) associated with desmin+ / ERTR-7+ (red and green) fibroblastic reticular cell (FRC) fibers; composite image of polyclonal B cells in a lymph node follicle (blue) and the migration tracks of wild-type (red) and SAP KO (green) T cells in the follicle and germinal center; dendritic cells (green) extending (‘balloon bodies”) into the gut lumen from beneath the villus epithelial cell layer (red); and activated T cells (green) in a BCG-induced liver granuloma surrounded by intact liver sinusoids (red blood tracer) and hepatocytes (blue nuclei). View a larger version.

 

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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Biography

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.

Research Group

photo of members of the Lymphocyte Biology Section
Left to right: Tim Laemmermann, Jianyong Tang, Tetsuya Honda, Michael Gerner, Judith Mandl (bottom row), Nienke Vrisekoop (top row), Ronald N. Germain (bottom row), Amanda Poholek (top row), Joao Monteiro (bottom row), Parizad Torabi-Parizi (top row), Menna Clatworthy (bottom row), Ina Ifrim (top row), Nick van Panhuys, Naeha Subramaniam, Zhidou Liu, Wolfgang Kastenmuller
 

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Selected Publications

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.

Visit PubMed for a complete publication list.

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Videos from LBS Research

A single z slice from an intravital four-dimensional data set showing numerous T cells (red) exiting HEV (green) in a lymph node via lucent areas that appear to be gaps in the FRC sheath (“exit ramps”). The playback speed is 300x for both the main and zoomed image. See 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.

 

Movie 2: T cells migrate along the FRC network

 

Movie 3: Preferential interactions of naive CD8 T cells with CD4 T cell-engaged vs. non-engaged DCs

 

Movie 4: Behaviors of recent immigrant B cells in and around peri-HEV DC arrays loaded with or without cognate Ag (Quicktime)

 

Movie 5: Distinct behaviors of MD4 and non-tg B cells in an LN containing HEL-DCs

 

Movie 6: Differential adhesion of Sap +/+ and Sap -/- T cells to antigen-presenting B cells

 

Movie 7: Sap -/- OT-2 T cells fail to stably interact with B cells in the absence of competition from Sap +/+ OT-2 in vivo

 

Movie 8: Sap -/- T cells fail to be recruited and retained in nascent GC

 

Movie 9: Three-dimensional reconstruction of DC extensions across the epithelial layer of the terminal ileum

 

Movie 10: Different shape of trans-epithelial DC extensions

 

Movie 11: Rapid association of blood-borne BCG with Kupffer cells observed in MHCII-EGFP mice

 

Movie 12: T cells appear to migrate along macrophage cell bodies at the granuloma periphery

 

Movie 13: Directional extravasation of neutrophils from blood vessels toward the site of skin damage and parasite deposition

 

Movie 14: Magnified view of a portion of Movie 13

 

Movie 15: Sequential migration of neutrophils from the epidermis/dermis into sites of sand fly proboscis penetration through the stratum corneum

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Last Updated June 18, 2014