The Journal of Experimental Medicine
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Published 21 July 2003. doi:10.1084/jem.20030422
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© Rockefeller University Press, 0022-1007/2003/7/235 $5.00
The Journal of Experimental Medicine, Volume 198, Number 2, 235-247

Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

Sayuri Yamazaki1, Tomonori Iyoda2, Kristin Tarbell1, Kara Olson1, Klara Velinzon1, Kayo Inaba2 and Ralph M. Steinman1

1 Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
2 Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan

Address correspondence to Ralph M. Steinman, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021. Phone: 212-327-8106; Fax: 212-327-8875; E-mail: steinma{at}mail.rockefeller.edu

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25- autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25- CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25- CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25- CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

Key Words: dendritic cells • CD25+ CD4+ regulatory T cells • anergy • IL-2 • CD86


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