Abstract
Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-β and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-κB (NF-κB) activity in reporter assays which is in keeping with a constitutive NF-κB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.
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Acknowledgements
This work was supported by grants from The University of Copenhagen, The Scientific Faculty, The Danish Research Councils, The Foundation of 17-12-1981, The Novo Nordic Foundation, The Danish Cancer Society, Neye Fonden, The Lundbeck Foundation, The Leo Pharma Foundation, and The National Cancer Institute-CA89194 (MA Wasik). We thank Keld Kaltoft (Århus University and CellCure Århus, Denmark) for the generous gift of MF, MySi and SeAx cell lines. Approval was obtained from the University of Copenhagen for these studies. Informed consent was provided according to the Declaration of Helsinki Principles. The project part concerning the establishment and study of CTCL cell lines by Dr Keld Kaltoft has been approved by ‘Den videnskabsetiske Kommite i Århus Amt’ (The science-ethical committee in Århus County).
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Krejsgaard, T., Gjerdrum, L., Ralfkiaer, E. et al. Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome. Leukemia 22, 2230–2239 (2008). https://doi.org/10.1038/leu.2008.224
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DOI: https://doi.org/10.1038/leu.2008.224
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