Cloning and Characterization of NF-ATc and NF-ATp : The Cytoplasmic Components of NF-AT

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Abstract

Signalling through the T cell antigen receptor initiates a complex series of events resulting in the activation of a group of genes (early genes) that are involved in the proliferation of T cells, the development of immune function and a variety of cellular interactions that contribute to immune responses1,2. In addition, signalling through the antigen receptor is essential for several transitions in thymic development. These findings raise the question of how such diverse responses are brought about by the actions of a single receptor. Several years ago, we identified nuclear response elements for these signals in the IL-2 promoter/enhancer3–6. In the IL-2 genes, two such sites were identified that bound a protein complex that we called NF-AT after the selective expression of this complex in nuclear extracts of activated T cells5. The sequence to which this protein bound was shown to direct transcription to activated T cells in the context of a transgenic mouse7. Furthermore, transcription directed by the NF-AT binding sites required proper presentation of antigen by MHC matched cells8. These finding indicated that this protein might serve as a general terminus for signals coming from the antigen receptor and thereby aid in the elucidation of the signalling pathway carrying information from the cell membrane to the nucleus. Despite many efforts to characterize this protein, it has been elusive; indeed, it has been inferred to be a Pu protein, ets-1, elk-1, a 28 kDa protein and a 57 kDa protein. None of these proteins appear to be actually involved in the biologic activity attributed to this complex. Direct purification of the protein from bovine thymus has revealed that it is composed of two cytosolic components, NF-ATc and NF-ATp, which bear a vague similarity to a limited region of the rel/Dorsal family, but it is otherwise a pioneer protein9,10.