Research focuses on the molecular, cellular, and genetic underpinnings of immune system function and development, on host-pathogen interactions, and on a variety of autoimmune disorders. In addition to the growing need to apply basic science research towards human disease, we have developed a Human Translational Immunology (HTI) Section to improve our understanding and treatment of human immunological disorders. The general research interests of the Immunology Track break down into six major themes, spanning almost all aspects of the immune system and its role in disease prevention.
B and T Cell Effector and Memory Cell Differentiation
Upon activation T and B cells differentiate into effector cells that perform critical effector functions such as producing cytotoxic antipathogen molecules and antibodies, respectively. They also migrate to the site of infection and produce chemokines to recruit additional immune cells to eliminate infected cells. After successful completion of infection, a small fraction of the cells develop into long-lived memory T and B cells that protect against reinfection.
Computational immunology (or systems immunology) involves the development and application of bioinformatics methods, mathematical models and statistical techniques for the study of immune system biology. The immune system is composed of dozens of different cell types and hundreds of intersecting molecular pathways and signals. Systems approaches can be used to predict how the immune system will respond to a particular infection or vaccination. Or it can help understand how best to design an immunotherapy -- will it help ease disease and what might the side effects be? In addition, computational approaches are increasingly vital to understand the implications of the wealth of gene expression and epigenomics data being gathered from immune cells. Yale has a diverse research program in computational immunology that brings together expertise from a variety of scientific disciplines to bear on research projects in vaccine response, host-pathogen dynamics, cell-fate choices, immune genomics, informatics, and many other topics. Students interested in computational immunology can be co-mentored by faculty from the Immunology and Computational Biology and Bioinformatics Tracks.
Consequences of an Immune Response
Apart from the obvious consequence of the elimination of an invading organism, an appropriate immune response results in immunological memory and large numbers of activated lymphocytes, which must be eliminated. The mechanisms controlling immunological memory, tolerance, and apoptosis, as well as those leading to autoimmunity, are a major interest of many faculty. Diabetes, multiple sclerosis, lupus, and rheumatoid arthritis are just some of the autoimmune diseases under study. Much of this work takes place in the context of the new Section of Human and Translational Immunology.
Infectious Disease and Host-Pathogen Interaction
A major interest is the study of infectious organisms—bacterial, viral and parasitic—and the immune response to them. A great deal of effort is directed toward understanding the way in which the immune system recognizes and elicits an immune response against the pathogens. In addition, there is a strong interest in developing strategies used by infectious agents to avoid the immune system. HIV, hepatitis B virus (HBV), Hepaptitis C virus (HCV) herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV), West Nile virus (WNV), influenza, vaccinia virus (VV), parvoviruses, Candida albicans, Borrelia burgdorferi (the causative agent of Lyme Disease), Listeria monocytogenes, Leishmania, Streptococcus pneumoniae, and Legionella pneumophilia are all under study.
A central focus of research is to understand the molecular events underlying the development of B and T lymphocytes. Areas of major interest include the receptors and signals that control lymphocyte lineage commitment, cell maturation, cell proliferation, and cell death; the establishment of the proper environments for lymphocyte development; mechanisms that regulate the state of chromatin during lymphocyte development; and the mechanisms by which antibody and T cell receptor genes are assembled and diversified.
Mounting an Immune Response
An effective immune response requires the coordinated action of numerous cell types. A critical first step is the activation of cells of the innate immune system, including monocytes, macrophages, dendritic cells, and neutrophils; and the receptors and signaling molecules that control this process are under intensive study. The mechanism by which cells take up, process, and present antigen is a major interest, as is the recognition of this antigen by T cell receptors on T lymphocytes. Cytoplasmic signal transduction molecules, nuclear transcription factors, and mechanisms controlling gene expression are all under study.
Regulating the Immune Response
The immune response is tightly regulated through the interaction of cell surface receptors with secreted cytokines and with one another, and the mechanisms by which these interactions exert their regulatory influences are studied in several laboratories. Another major interest is in learning how specialized cells or anatomic locations, such as vascular endothelial cells or the epidermis, regulate and direct the immune response.
Structural Analysis of Immune System Receptors and Effectors
There is a growing interest in using structural approaches to understand the function of key molecules of the immune response. For example, a major effort is devoted towards understanding how the Toll-like receptors, despite their similarity in extracellular-ligand recognition regions, are able to specifically recognize such a wide variety of pathogen associated molecular patterns (PAMPS). Another effort is aimed at understanding the mechanism of APOBEC enzymes in controlling viruses such as HIV.
More than thirty laboratories are actively involved in research in immunology. Many share immediately adjoining or nearby laboratory space on the top three floors of The Anlyan Center (TAC), and five faculty are funded by the Howard Hughes Medical Institute. The Department of Immunobiology provides one of the largest integrated training programs in immunology in the country, led by a faculty with a reputation for excellence in research. The Department of Immunobiology maintains a wide variety of major equipment, and Dr. Richard Flavell, chair of the Department, oversees a very active transgenic mouse/ES cell/knockout facility to which members of the Department have access. In addition, the department houses the flow cytometry core which contains several state-of-the art flow cytometers and cell sorters.