The Roles of Major Histocompatibility Complex Class I and Foxk1 in Natural Killer Cell Development

Pathways leading to the development of functionally mature Natural Killer cells from bone marrow progenitors are incompletely characterized. Several reports have indicated the necessity of class I Major Histocompatibility Complex-Ly49 interactions to generate functionally mature Natural Killer cells. Natural Killer cells from mice deficient in Major Histocompatibility Complex class I exhibit impaired lytic ability against class I+and class I- targets. It has been proposed that class I interactions with inhibitory Ly49s are required for generation of lytic Natural Killer cells; cells that do not receive these signals fail to become activated. To investigate further the role of class I-Natural Killer cell interactions during development, we produced chimeric mice using class I- mice, in which the hematopoietic system was derived from class I-expressing mice. We discovered that class I+ Natural Killer cells that are developed in a class I- environment are not functional, despite the presence of class I on hematopoietic cells. This indicates that the environment in which Natural Killer cells are developed determines their function and further supports the role of the bone marrow microenvironment in Natural Killer cell development. A complete understanding of Natural Killer cell development would involve determining which transcription factors drive development of Natural Killer cells from stem cells to mature, functional Natural Killer cells. Several transcription factors have been described to be necessary for Natural Killer cell development. Mice lacking these transcription factors often have a deficit in Natural Killer cells in vivo. Here we illustrate a role for the forkhead transcription factor, Foxk1, in Natural Killer cell development. Foxk1-/- mice have significantly fewer Natural Killer cells than do wild-type mice and their remaining Natural Killer cells have decreased cytotoxicity. An increase in the percentage of cells in a developmentally important expansion stage indicates that Foxk1 acts there. However, Foxk1 seems to play no role in the thymic development of Natural Killer cells; cells with phenotypic characteristics of thymus-derived Natural Killer cells are present in Foxk1-/- mice. Our studies show a clear role for Major Histocompatibility Complex class I and Foxk1 in the development of functionally mature Natural Killer cells in mice.