Transcription Factors that Specify Natural Killer Cell Fate and Function

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): Natural killer (NK) cells are lymphocytes that participate in the immune response against viruses, bacteria, parasites, tumors, and transplants. Their development can be classified into genetically separable stages that are governed by the T-box transcription factors T-bet and Eomesodermin (Eomes). NK cells have long been categorized as innate immune cells because they lack expression of the proteins that are necessary to assemble diverse T- and B-lymphocyte antigen receptors. NK cells discriminate between healthy and harmful somatic cells in a different manner from other lymphocytes, but how they become educated to make this distinction during development is not completely understood. This project, in 3 aims, seeks to expand on our current understanding of the signals that shape the maturation of NK cells to distinct stages with the necessary education to partake in immune defense under the right circumstances. The first aim will determine whether NK cell maturation can be blocked by conditional overexpression of T-bet, a transcription factor that is associated with the maintenance of immature NK cells. The second aim will employ a transgenic mouse model, in which Eomes is ectopically expressed under the control of T-bet regulatory elements, to examine whether forcing precocious NK cell maturation in organs typically devoid of mature NK cells will perturb NK cell education, self-tolerance, and function. The third aim will utilize various genetic models of T-bet and Eomes deficiency to assess the potential role of these transcription factors in mobilizing NK cell recall responses. The successful execution of these aims may promote the development of NK cell therapies against cancer and infectious diseases.