The balance of naive, effector Th1 and Th2 and memory CD4+ T cells is critical for the course of an immune response. Differences in cytokine production, activation signal requirement, surface maker expression and life span characterize these stages of CD4+ T cells, but little is known about the molecular mechanisms that determine these phenotype characteristics. This project represents an effort to define the regulation and the role of the transcription factor NFAT in the differentiation and activation of naive, effector and memory CD4+ T cells. Our previous studies have demonstrated that the regulation of the activity of specific transcription factors depends on the differentiation stage of cells. We have shown that AP-1 and NFAT can mediate transcription in effector Th2 cells, but not in Th1 cells. AP-1- and NFAT-mediated transcription requires T cell receptor (TcR) and co-stimulatory signals in naive CD4+ T cells, while only TcR-mediated signals are required in effector Th2 cells. The presence of JunB in AP-1 complexes appears to be relevant for the specific regulation of AP-1 transcriptional activity in Th2 cells. In this project we propose to extend these studies to determine how NFAT transcriptional activity is regulated during the development of memory cells for naive and effector CD4+ cells, specifically gene expression, DNA binding, and nuclear translocation of the different NFAT family members (Aim 1). Our preliminary data suggest that the relative ratio of two components of the NFAT family, NFAT1 and NFAT2, varies during the differentiation of CD4+ T cells and that can be one regulatory factor of NFAT-mediated transcription. We will determine whether changes in the NFAT1/NFAT2 ratio influence the expression of cytokine of activation/death molecule gene in vitro, by overexpressing NFAT2 in CD4+ T cell clones (Aim 2). To determine the physiological relevance of NFAT1/NFAT2 ratio on the generation, activation and survival of naive, effector and memory CD4+ T cells in vivo, we will overexpress NFAT2 selectively in T cells in an inducible manner using transgenic mice (Aim 3). We believe that these studies will provide new insights about the importance of NFAT in the control of effector and memory immune responses.
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