International Immunology Advance Access originally published online on February 27, 2007
International Immunology 2007 19(4):345-354; doi:10.1093/intimm/dxm014
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Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production
1 Department of Surgery, University of British Columbia, and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, 2660 Oak Street, Vancouver, Canada
2 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, Milan, Italy
3 Department of Medicine, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada
4 Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy
Correspondence to: M. K. Levings; E-mail: mlevings{at}interchange.ubc.ca
Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD4+CD25+ T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines. We found that all dividing Teff cells expressed FOXP3, but only transiently, and at levels that were significantly lower than those in suppressive nTregs. This temporary expression in Teff cells was insufficient to suppress expression of reported targets of FOXP3 repressor activity, including CD127, IL-2 and IFN-
, and was not correlated with induction of a nTreg phenotype. Thus expression of FOXP3 is a normal consequence of CD4+ T cell activation and, in humans, it can no longer be used as an exclusive marker of nTregs. These data indicate that our current understanding of how FOXP3 contributes to immune tolerance in humans needs to be re-evaluated.
Keywords: human, T cells, T cell activation, tolerance, transcription factors
Received 11 December 2006, accepted 24 January 2007.
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 J. E. Lopes, D. M. Soper, and S. F. Ziegler Foxp3 Is Required Throughout the Life of a Regulatory T Cell Sci. Signal., July 3, 2007; 2007(393): pe36 - pe36. [Abstract] [Full Text] [PDF]
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