T Lymphocyte based functional genomics of inflammation

Vanderbilt University, Nashville TN

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Abstract

Many inflammatory diseases of the heart, lung and vasculature are driven by T lymphocyte effector functions. Examples include atopic asthma, hypersensitivity pneumonitides, idiopathic granuloma formation (sarcoidosis), interstitial fibrosis and autoimmune cardiomyopathies. Among T lineage cells, essential functional characteristics depend on differential into subsets of effector cells, including T helper (Th) 1 and Th2 subsets for CD4+T cells, cytotoxic T lymphocytes (CTL), and natural killer T (NKT) cells. Each of these subsets play distinct functional roles in inflammatory diseases. Prior gene targeting studies of cell surface proteins, intracellular signal transducers, and inducible transcription factors have revealed important insights into T cell- mediated inflammation, underscoring the value of genetically manipulated mouse strains in understanding this process. Despite these advances, much remains to be learned about the function of newly sequenced genes in T cell-mediated inflammation. The long term goal of the T cell Project of this Program is to identify and functionally characterize a set of genes that are important contributors to T lymphocyte functions and the regulation of T cell-dependent inflammation. To this end, we will utilize a large library of embryonic stem (ES) cell clones harboring retroviral insertions. The trapped genes in this library will be displayed on DNA microarrays to determine their expression patterns and potential roles in T cell-mediated inflammation. ES cell clones with relevant primary sequences and/or expression patterns will be selected for transmission into the murine germline. Novel mutant mouse strains will be analyzed phenotypically to investigate the role of mutant genes in T lymphocyte development, activation, and differentiation, as well as T lymphocyte-based inflammation. At the completion of this project we expect to have generated and characterized a novel set of mutant mouse strains with either heightened or attenuated T cell-mediated inflammatory responses. Studies of these genetically altered mice will provide insights regarding the molecular mechanisms that control T lymphocyte-mediated inflammation. We anticipate that the pathological abnormalities in a subset of these animals will have similarities with important disease processes in humans, thus providing unprecedented in vivo experimental models to study human inflammatory diseases. The novel genes identified in these studies will also provide novel molecular targets for therapeutic intervention in inflammatory diseases.