Area of Research: Basic Immunology/Virology Though the existence of immunological “memory,” which enables the immune system to “remember” infections and respond accordingly, has been recognized for centuries, our understanding of the cellular and molecular basis of this type of memory remains limited. As a basic immunologist, Dr. Joshy Jacob seeks to understand B cell memory. Studying memory B cells has been difficult because these cells cannot be unambiguously identified as they lack specific, permanent cell surface markers. To bridge this gap, Dr. Jacob developed a novel transgenic mouse model system that permanently “tags” and identifies memory B cells. This model enables Dr. Jacob to characterize the complex processes by B cell memory is generated, regulated and maintained. Dr. Jacob also studies the phenomenon known as “original antigenic sin”. Humans previously exposed to influenza virus, upon infection with a novel influenza strain, produce antibodies directed primarily against the older viral strains at the expense of responses to novel protective antigenic determinants thus exacerbating the severity of current infection. This blind spot of the immune system and the redirection of responses to the “original antigen”, but not to the current virus is well established but poorly understood. Since original antigenic sin drastically dampens immune responses to newer strains of influenza virus, Dr. Jacob seeks to understand the fundamental aspects of this phenomenon such that vaccines capable of overcoming original antigenic sin can be designed. Dr. Jacob is an Assistant Professor in the Emory School of Medicine Department of Microbiology and Immunology. He received his Ph.D. in immunology from the University of Maryland School of Medicine at Baltimore, and did his post-doctoral training at the Rockefeller University and the Massachusetts Institute of Technology. Research The immune system is remarkable in its ability to mount responses against a wide array of antigens and to respond with enhanced vigor to antigens encountered in the past. This exaggerated recall immune response, or immune memory, is a central concept in immunology. It forms the basis of vaccination against infectious diseases. Immune memory is mediated by memory lymphocytes that persist in the host long after resolution of the infection or antigenic insult. The long-range goal of our lab is to understand how immune memory is generated, regulated, and maintained. To study immune memory, we have generated a novel and powerful transgenic mouse model system. In this system, both effector and memory pools of T lymphocytes are indelibly tagged with the marker b galactosidase by an irreversible genetic recombination event. This allows us to map the fate of activated CD4 and CD8 T cells in vivo. We use this model system to probe lymphocytic choriomeningitis (LCMV) virus-induced immune responses and the differentiation pathway of immune memory generation. We are also interested in following the fate of antigen-bearing dendritic cells (DC) in vivo. DCs are highly potent antigen-presenting cells and the functions as key regulators of immune responses. They initiate antigen-specific immune responses by acquiring antigens in peripheral tissues, migrating to lymphoid organs, and presenting these antigens as processed peptides to T cells. Despite its critical role, the persistence, phenotype, and clonal dynamics of antigen-bearing DCs involved in initiating an immune response remains unclear. We have used cre-lox recombination to permanently mark antigen-bearing dendritic cells at the site of immunization (abdominal epidermis) and track them in the draining lymph nodes. Interestingly, following gene gun immunization, we found that the number of antigen-bearing dendritic cells in the draining lymph node is one hundred times higher than previous estimates. These antigen-bearing DCs that migrate to the lymph nodes from the skin are CD11c+, CD11b+, CD86+, class II MHChi, CD4-, CD8- myeloid DCs, and they persist for approximately two weeks.
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