The Journal of Experimental Medicine
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Published online 4 June 2001.
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© The Rockefeller University Press, 0022-1007/2001/6/1295/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 11, June 4, 2001 1295-1302

Brief Definitive Report

Human CD25+CD4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded In Vitro without Loss of Function

Megan K. Levingsa, Romina Sangregorioa, and Maria-Grazia Roncaroloa
a San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy 20132

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

Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4+ Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25+CD4+ Tr cells in humans has not been reported. Here we show that human CD25+CD4+ Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor–mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte–associated antigen (CTLA)-4. Human CD25+CD4+ Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-ß, low levels of interferon (IFN)-{gamma}, and no IL-4 or IL-2. Importantly, CD25+CD4+ Tr cells strongly inhibited the proliferative responses of both naive and memory CD4+ T cells to alloantigens, but neither IL-10, TGF-ß, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25+CD4+ Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25+CD4+ Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell–mediated diseases.

Key Words: suppressor, T lymphocytes, immune tolerance, CTLA-4, IL-2 receptor {alpha} chain, human


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