The Journal of Experimental Medicine
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Published online 11 November 2002 doi:10.1084/jem.20021139
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© Rockefeller University Press, 0022-1007/2002/11/1335/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 10, November 18, 2002 1335-1346
Human CD25+CD4+ T Suppressor Cell Clones Produce Transforming Growth Factor ß, but not Interleukin 10, and Are Distinct from Type 1 T Regulatory Cells

Megan K. Levings1, Romina Sangregorio1, Claudia Sartirana1, Anna Lisa Moschin1, Manuela Battaglia1, Paul C. Orban2 and Maria-Grazia Roncarolo1,3

1 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, Milan 20132, Italy
2 San Raffaele Scientific Institute, Via Olgettina 58, Milan 20132, Italy
3 Universitá Vita-Saluk San Raffale, Via Olgettina 58, Milan 20132, Italy

Address correspondence to Maria-Grazia Roncarolo, San Raffaele Telethon Institute for Gene Therapy, Via Olgettina 58, Milan 20132, Italy. Phone: 39-02-2643-4702; Fax: 39-02-2643-4668; E-mail: m.roncarolo{at}hsr.it

T regulatory (Tr) cells are essential for the induction of peripheral tolerance. Several types of Tr cells exist, including CD4+ T cells which express CD25 constitutively and suppress immune responses via direct cell-to-cell interactions, and type 1 T regulatory (Tr1) cells, which function via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-ß. The relationship between CD25+CD4+ T cells and Tr1 cells remains unclear. Here, we demonstrate at the clonal level that Tr1 and CD25+CD4+ T cells are two distinct subsets of regulatory cells with different cytokine production profiles. Furthermore, CD25-CD4+ T cells can be rendered anergic by IL-10 and differentiated into Tr1 cells in the absence of CD25+CD4+ T cells. Cloned human CD25+CD4+ T cell populations are heterogeneous and only a subset of clones continues to express high levels of CD25 and is suppressive. The intensity of CD25, cytotoxic T lymphocyte antigen (CTLA)-4, and glucocorticoid-induced tumor necrosis factor (TNF) receptor expression correlates with the suppressive capacity of the T cell clones. None of the CD25+CD4+ T cell clones with suppressive function produce IL-10, but all produce TGF-ß. Suppression mediated by CD25+CD4+ T cell clones is partially dependent on TGF-ß, but not on constitutive high expression of CD25. Together these data indicate that naturally occurring human CD25+CD4+ T cells are distinct from IL-10–producing Tr1 cells.

Key Words: suppressor T lymphocytes • IL-10 • TGF-ß • interleukin 2 receptor {alpha} chain • Tr1


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