The immune system is involved in a remarkably wide variety of disease processes, either directly, through an aberrant immune response (as seen for example in autoimmune diseases), or indirectly, through an insufficient immune response (as seen for example in cancer or various infectious processes). The rational development of strategies and therapies that modulate the immune response for clinically beneficial purposes requires a detailed understanding of the molecular mechanisms involved in the function of T lymphocytes, as it is these cells that play a pivotal role in the molecular events regulating immediate early gene expression in T lymphocytes after antigen receptor stimulation by studying the recently cloned NFATc gene which encodes a transcription factor representing the cytosolic component of the nuclear factor of activate T cells, a DNA binding complex involved in the regulated expression of lymphokine genes such as interleukin 2. An understanding of the regulation of the NFATc gene is of particular importance in further understanding the molecular mechanisms controlling gene expression in T lymphocytes because, not only is its expression restricted to lymphoid tissues, but it is rapidly induced upon T cell activation in a cyclosporin A/FK506-sensitive manner, thus representing an immediate early gene that may be the direct nuclear target of signals emanating from the T cell antigen receptor complex or other regulatory plasma membrane receptors. The NFATc gene will be studied by characterization of signal requirements for inducible NFATc RNA and protein expression. Subsequently, the molecular mechanisms regulating the expression of the NFATc gene will be determined through the elucidation of the NFATc promoter and functional analysis of the NFATc gene transcriptional regulatory sequences, thereby identifying additional DNA binding regulatory proteins that may act as targets of T cell signal transduction. Additionally, NFATc and a recently cloned gene NFATp encode a 280 amino acid region of homology which defines a novel family or subfamily of transcription factors that exhibit limited similarity to the dorsal/rel/NFkappaB family of transcription factors. As the two known NFAT family members, as well as rel family members, are targets of signal transduction pathways, the hypothesis that the NFAT rel similarity region (RSR) is shared by other signal-targeted transcription factors will be tested through the identification of additional NFAT family members that contain the NFAT RSR based on DNA sequence homology. Such genes identified by homology to the NFAT RSR may therefore represent novel signal targeted transcription factors. As a result of the line of investigation proposed here, a more detailed understanding of the mechanisms regulating gene expression in T lymphocytes will be obtained that can potentially be applied toward controlling the immune system therapeutically.
