Evolution of Immune Loci Critical in Antigen Recognition

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This project focuses on the evolution of the adaptive immune system, which enables animals to respond powerfully and specifically to pathogens of many different types. A key feature of adaptive immunity is antigen recognition by two types of antigen receptors: antibodies (immunoglobulins, produced by B cells, and the source of humoral immunity), and T-cell receptors (TCR; involved in cellular immunity). Because of their extraordinary diversity, these receptors can bind to a wide range of biological molecules; receptor diversity is created by unique genetic mechanisms (somatic gene rearrangement and hypermutation) characteristic of the adaptive immune response. Previous work has shown that the oldest jawed vertebrates on earth, the cartilaginous fish (including sharks), have all of the basic molecular hardware of this system. However, some elements of the mammalian adaptive immune system - lymph nodes, bone marrow, and specialized lymphoid tissue such as germinal centers - are absent in sharks; sharks thus provide a relatively simple model to understand the most fundamental characteristics of adaptive immunity. Although T cells and B cells have been considered quite distinct in function, this laboratory discovered in shark cells an antigen receptor, NAR-TCR, that uses the same domain in both cellular (TCR) and humoral (antibody) immunity; it has also now documented multiple instances of shark T-cells with properties (e.g., immunoglobulin variable domains and somatic hypermutation) previously ascribed only to B-cells. Building on these findings, this project will reexamine the basic definition of vertebrate B and T cells by exploring the boundaries of the immunogenetic mechanisms available to each cell type. The unexpected plasticity of these boundaries offers provocative new perspectives on the evolution of the vertebrate immune system; it also suggests new possibilities for immune response manipulation in other vertebrates, including humans. Student research training from high school through graduate levels is integral to the project.