GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

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T cell tolerance has been found to occur in immature T cells in the thymus and also extrathymically in mature T cells. Our studies of mature T tolerance has revealed that they may undergo deletion or enter a functionally unresponsive state termed anergy. In anergy, a T-helper cell can be induced to "turn off" IL-2 production if it is stimulated through its T-cell receptor in the absence of costimulation. Previously we showed that regulatory proteins that govern IL-2 gene expression may be poorly activatable in response to antigen in anergic T cells. One important determinant of whether T cells will be normally activated by encountering an antigen/MHC complex is whether it is presented along with a co-stimulatory stimulus. Co-stimulation is the signal provided by the interaction of surface molecules such as CD28 (on the T cell) and B7 or BB-1 (on the antigen-presenting cell). The presence of co-stimulation seems to be required for the normal T cell proliferative response to antigen. To understand the role of co-stimulation in IL-2 production, we have studied the effects of co-stimulation on various elements in the IL-2 promoter. Thus far these studies indicate that the transcriptional function of certain cis elements in the promoter can be augmented by co- stimulatory influences. Further studies are in progress to further define the molecular mechanisms involved. Finally, an important aspect of the success of an immune response to an invading micro-organism appears to be the specialization of the helper T cell response towards cells that either produce IL-2 (TH1 cells) or IL-4 (TH2 cells). We have studied the regulatory elements in the promoter of the IL-4 gene and detected a transcriptional trans-activator and its binding site (CS-1) that are restricted to and crucial for expression in TH2 cells.