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International Immunology Advance Access originally published online on February 12, 2008
International Immunology 2008 20(3):421-431; doi:10.1093/intimm/dxn002
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25– effector T cells

Laura Passerini1, Sarah E. Allan2, Manuela Battaglia1, Sara Di Nunzio1, Alicia N. Alstad2, Megan K. Levings2, Maria G. Roncarolo1,3 and Rosa Bacchetta1

1 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132 Milan, Italy
2 Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, British Columbia V6H 3Z6, Canada
3 Vita-Salute San Raffaele University, Milan, Italy

Correspondence to: M. G. Roncarolo; E-mail: m.roncarolo{at}hsr.it

Forkhead box P3 (FOXP3) is considered a specific marker for CD4+CD25+ regulatory T (Treg) cells, but increasing evidence suggests that human CD4+CD25– effector T (Teff) cells can transiently express FOXP3 upon activation. We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cells. In contrast, cytokines which do not activate STAT5, such as IL-4 or transforming growth factor-β alone, do not directly induce FOXP3 expression in activated Teff cells. Moreover, expression of a constitutively active form of STAT5a is sufficient to induce FOXP3 expression in Teff cells. Expression of FOXP3 in activated Teff cells requires both TCR-mediated activation and endogenous IL-2, but is not dependent on cell division and does not induce suppressive function. The presence of STAT5-activating cytokines is also required to maintain high FOXP3 expression and suppressive activity of Treg cells in vitro. These data indicate that activation of STAT5 sustains FOXP3 expression in both Treg and Teff cells and contribute to our understanding of how cytokines affect the expression of FOXP3.

Keywords: {gamma}-chain signaling cytokines, suppressive activity, transcription factor

Transmitting editor: C. Terhorst

Received 6 August 2007, accepted 4 January 2008.


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