PU.1 is an ETS family transcription factor that is crucial for the development of multiple hematopoietic lineages including macrophages, B cells, mast cells and neutrophils. T cell development in PU.1-deficient mice is attenuated and the early lethality as well as the inability to generate PU.1-deficient T cells in multiple chimera models has hampered the analysis of the role of PU.1 in mature T cells. PU.1 expression patterns often appear opposite that of GATA family factors. Since GATA3 expression is modulated during T helper cell development, we investigated PU.1 expression in T helper subsets. Contradicting previous observations that PU.1 is not expressed in T cells, we observed PU.1 expression in Th2 cells but not in Th1 cells. Strikingly, PU.1 is expressed in populations of Th2 cultures that have low expression of particular Th2 cytokines. Furthermore, retroviral expression of PU.1 in Th2 populations decreases secretion of Th2 cytokines. Preliminary experiments suggest that PU.1 may regulate the Th2 phenotype by interfering with GATA3 function. The goal of this application is to define the role of PU.1 in Th2 regulation and to elucidate the mechanism of interference with the development of the Th2 phenotype. Our hypothesis is that PU.1 is an important regulator of Th2 function. We will investigate this issue by examining PU.1 gene targeted mice and determining the Th2 phenotype by assessing both in vitro and in vivo T helper cell population development. We will also examine the structural requirements for PU.1 function in Th2 cells and how PU.1 may regulate GATA3 and other Th2-regulating factor function. We have identified PU.1 as a Th2-restricted negative regulatory factor of Th2 cytokine secretion. Regulation of PU.1 expression and function could be manipulated as a treatment for Th2 mediated diseases including asthma and allergies.
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