Evolution of Diversification Mechanisms for Lymphocyte Antigen-Receptors
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abstract
Vertebrates share an adaptive immune system that is capable of great specificity in responding to pathogenic threats and a remarkable memory for previous challenges. Lymphocytes, the blood cells that mediate adaptive immunity, come in two types: B cells that secrete antibodies, and T cells that direct other immune effectors and kill infected or cancerous cells. Both B and T lymphocytes exist as vast populations in which each cell has a unique antigen receptor that is the product of DNA recombination processes. Humans have distinct genes, receptors, and diversification mechanisms that are separately employed by T cells and B cells. However, in sharks, which represent the oldest organisms with an adaptive lymphocyte system, the line between B and T lymphocytes is much blurrier. Shark B and T cells have greater plasticity to use genes, receptor modules, and receptor diversification methods that are strictly B or T lineage-specific in humans. In this project, the development of T cells in the shark will be studied in detail, including the role of a mechanism of generating mutations in these cells. The results will yield greater insight into the fundamentals of how vertebrates orchestrate adaptive immunity, in the process yielding new thinking and tools for vaccine design and immunotherapeutics. The project will contribute to STEM education through the participation of undergraduates and high school students in the research, utilizing an iterative program of teaching and hands-on research experience in collaboration with a local high school teacher. The central hypothesis of the project is that T cell receptors retain significant, ancestral, functional plasticity in the shark, evident by the organization of the antigen receptor loci, the immunogenetic processes acting upon the genes therein, development of the cells in the thymus, and the transcription profiles of the cells that express these receptors. This functional plasticity should be evident in more derived vertebrate antigen receptor diversification systems as well as in the basal shark. The central hypothesis will be tested by pursuing two aims: 1) Determine how T cells employing immunoglobulin variable genes develop in primary lymphoid tissues, diversify repertoire, are transcriptionally controlled, and whether they function more as B or T cells and 2) Identify the extent, regulation and physiological role of somatic hypermutation (SHM) at shark T cell receptor loci in both áâ and ãä T cells, and explore the boundaries of activation- induced cytidine deaminase (AID) function. The following expected outcomes are anticipated: the first aim will determine if B and T cell variable gene segments are inherently interchangeable, if the cells bearing immunoglobulin-T cell chimeric receptors develop in the thymus, if the transcriptional profile of the cells is more B- or T-like, and what they contribute to immunity. The second aim will define if thymic and peripheral SHM of T cell receptors operates for repertoire diversification, passage of thymic selection, or affinity maturation at the á and ã loci, and better define reactions catalyzed by AID.
