The increase in T cell numbers associated with Sezary Syndrome likely occurs as a result of hyperproliferation as well as decreased apoptosis. The mechanisms involved resulting in these effects however are not clearly understood. We have previously reported that IL-16 is a bi-functional protein involved in regulation of T cell growth. The secreted (mature) portion has been classified as a competence factor that regulates T cell growth through extracellular association with CD4, promoting CD25 expression and transition from the G0 phase to G1. The pro-piece (pro-IL-16) has been recently detected in the nucleus of T cells where it affects proliferation through the regulation of Skp-2 transcription. Pro-IL-16 functions as a scaffold protein which interacts with co- factors GABP1 and HDAC-3 to suppress Skp2 transcription, therefore indirectly regulating degradation of one of the major cyclin kinase inhibitors associated with T cell proliferation, p27kip1. Our preliminary data now indicates that in T cells from CTCL patients there is an initial redistribution of intracellular pro-IL-16 characterized by preferential loss in the nucleus. This loss can be attributable to mutations in the PDZ1 domain, correlating to loss of binding by the nuclear chaperone protein HSC70. The loss of nuclear pro-IL-16 also appears to be combined with an observed increase in secretion of mature IL-16 in stages I-III as intracellular stores become depleted. In addition, there is an overall progressive reduction in the production of IL-16 that may be associated with promoter hypermethylation. It is our hypothesis therefore that the onset of CTCL is associated with hypermethylation of the IL-16 promoter resulting in a progressive reduction in protein production. In addition, mutations in PDZ1 of pro-IL-16 results in loss of HSC70 binding, significantly reducing nuclear expression or function, while increasing secretion of mature protein. Secreted IL-16 interacts with surface expressed CD4 to further induce cell cycle progression in the malignant cells. In these studies we propose to investigate the effects of methylation on the IL-16 promoter as well as within the coding region;to delineate the mechanism by which pro-IL-16 is prevented from nuclear translocation and establish cellular effects of Sezary T cells following expression of wild type pro-IL-16;and finally to determine the role of secreted IL-16 on T cell proliferation and potential expansion of T regulatory cells.
We have shown that nuclear pro-IL-16 functions to regulate T cell progression within the cell cycle and that in Sezary T cells pro-IL-16 has lost the ability to translocate into the nucleus rendering the cells hyperproliferative. In these studies we propose to identity the mechanisms involved in regulating nuclear translocation of pro-IL-16;the ability of expressed wild type pro-IL-16 to regulate hyperproliferation in malignant T cells;and to investigate the role of secreted IL-16 to induce loss of tumor suppressor expression with resultant hyperproliferation. Completion of these studies will not only identify a mechanism for dysregulated growth in Sezary T cells but will elucidate a novel approach to potential therapeutics.
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