The normal immune system requires the capacity to regulate T-cell function, in order to resist the effects of pathogens and yet prevent the development of pathological autoimmune responses. Clonal anergy has been proposed as one potential mechanism for this control of immune reactivity in helper T cells. It is defined as a state of T-cell unresponsiveness that prevents their proliferation in response to antigen stimulation. Previous research has suggested that defective IL-2 production underlies this unresponsiveness, and this arises from of a block in signal transduction to the IL-2 gene enhancer. Working back from the nucleus, it has now been shown that: a) trans-activation at the IL-2 enhancer fails, b) AP-1 nuclear complex formation is defective, c) c-fos, fosB and junB expression cannot be induced and d) ERK, JNK and p38 activation are blocked, despite normal protein levels. Thus, a defect in signal transduction up-stream of MAPK activation at the level of coupling between the TCR/CD3 complex and p21 ras appears to be the cause of clonal anergy. Perhaps consistent with this, a heterokaryon analysis has demonstrated the presence of a dominant-acting repressor molecule in anergic T cells. Finally, our work has revealed a role for TCR and CD28 signal integration at the level of the Elk-I transcription factor, and this may prove to be an additional site of regulation by clonal anergy at the c-fos gene. With this new information, this research project will once again target the TCRJp2 1 ras/MAPK/AP- I /IL-2 gene signal transduction pathway for further investigation, and define those biochemical alterations that impair the expression of the IL-2 gene. Specifically, this research will: a) Determine the biochemical, molecular genetic and functional nature of TCR and CD28 signal integration at the level Elk-1/CBP trans-activation in normal and anergic Thl cells and b) Explore the nature of IL-2 gene repression in clonal anergy using a heterokaryon analysis. The information gained in this study will provide a better understanding of the biochemical mechanisms utilized by the immune system to regulate responsiveness to foreign and self-antigens, and may prove essential to the design of effective clinical therapies for infection, cancer and autoimmune diseases.
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