Productive activation of T cells requires integration of two signals: one, antigen specific, provided by the T cell receptor; and a second signal activated by the engagement of co-stimulatory receptors. Anergy, one of the mechanisms that accounts for establishment of peripheral tolerance, is evoked by an unbalanced activation of T cells through their antigen receptor without simultaneous engagement of co-stimulatory receptors. In this situation, T cells not only do not start a proliferative response, but they become unable to produce IL-2 and proliferate when re-stimulated with antigen in the presence of co-stimulation. Anergic stimuli produce a preferential activation of calcium signaling relative to other co-stimulation dependent signaling pathways. Under these conditions, members of the NFAT family of transcription factors are activated in the absence of their main transcriptional copartner, AP-1, directing the expression of a specific set of genes characteristic of the anergic response. We now propose to determine the mechanisms and consequences of the induction of anergy-associated programs of gene expression. The specific questions we will address are: 1) How is the expression of anergy-associated genes regulated? 2) What are the consequences of the activation of those genes? 3) Is the expression of anergy-associated genes able to induce T cell tolerance? To achieve these goals we propose three specific aims: 1) to study the nature of the NFAT complexes found on the promoters of those genes, differentiating them from those that bind to genes expressed during a productive immune response; 2) To determine the role of specific anergy-associated genes in the induction of T cell tolerance; and 3) to characterize the induction and maintenance of T cell anergy and its role in peripheral tolerance in a mouse model that constitutively activates the expression of anergy-associated genes. Defining the mechanisms that control the activation of a transcriptional program specific of T cell anergy and the molecular pathways affected by the expression of those genes should prove valuable to understand how immune tolerance is established and to define targets that will help design new therapeutic approaches for autoimmune diseases, organ transplant rejection and allergy.
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