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Published online before print February 12, 2008

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(Journal of Leukocyte Biology. 2008;83:1111-1117.)
© 2008 by Society for Leukocyte Biology

Differentiation of naive CD4+ T cells into CD4+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation

Milada Mahic^*,,1, Sheraz Yaqub^*,,1, Tone Bryn^*,, Karen Henjum^*,,, Dag M. Eide, Knut M. Torgersen^*,, Einar M. Aandahl^*, and Kjetil Taskén^*,,2

^* The Biotechnology Centre of Oslo,
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Norway;
Department of Gastroenterological Surgery, Ullevaal University Hospital, and
Norwegian Institute of Public Health, Oslo, Norway

²Correspondence: The Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, N-0349 Oslo, Norway. E-mail: kjetil.tasken{at}biotek.uio.no

Human CD4+CD25+ regulatory T (T_R) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring T_R cells develop in the thymus, adaptive T_R cells develop in the periphery from naive CD4+ T cells. Adaptive T_R cells may express cyclooxygenase type 2 (COX-2) and suppress effector T cells by a PGE₂-dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive T_R cells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25– T cells, the cells expressed FOXP3 and COX-2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time-points from Day 2, although suppression was merely present at Day 7. The adaptive T_R cells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF-β, IL-10, and PGE₂. However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.

Key Words: human • regulatory T cells (T_R cells) • immunoregulation • cyclooxygenase • TGF-β • IL-10-IL17

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