 Gene expression in memory CD4+T cells.
 Overview Appropriate T cell function is critical to immunity against infections, effective vaccine and tumor immunity. Dysregulation of T helper cell function, particularly the memory subset as defined by CD45RO, may be associated with diseases such as autoimmune diseases, failure of tumor surveillance and frank malignancy of T cells-cutaneous T cell lymphoma. Presently, there remains a lack of understanding in the molecular mechanisms governing memory T cells in normal function and in disease, particularly in humans. The gene of focus is CTLA-4, a co-stimulatory molecule with negative regulatory properties. This gene is induced during T cell activation, plays an important role in regulating T cell activation and affects the ability of T cells to respond to antigen. CTLA-4 binds to co-stimulatory molecules 137-1 and 137-2, and is related to CD28 structurally. In the absence of CTLA-4, there is profound immune dysregulation with uncontrolled lymphoproliferation of T cells. Their preliminary studies confirmed an increased level of CTLA-4 expression in memory T cells by approximately 7-fold. When memory CD4 T cells are stimulated, the expression of CTLA-4 shows a marked increase in comparison to naive CD4 T cells. These findings support the differential regulation of CTLA-4 expression between naive and memory T cells. Given the important role of CTLA-4 in controlling T cell function, the precise expression of CTLA-4 has critical implications in the immune response. This proposal describes experiments to investigate the regulation of CTLA-4 gene expression. Specifically, the aims will be: 1) to study the transcriptional regulation of CTLA-4 promoter, and 2) to study the regulation of CTLA-4 expression during differentiation of naive T cells to memory T cells. Understanding the mechanism regulating the differential expression of CTLA-4 may provide insights for the design of therapy to modulate CTLA-4 expression for control of immune response in inflammatory autoimmune diseases and for the development of vaccines.
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