Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction
- Sayuri Yamazaki*,
- Munjal Patel†,
- Alice Harper†,
- Anthony Bonito*,
- Hidehiro Fukuyama‡,
- Maggi Pack*,
- Kristin V. Tarbell*,
- Mia Talmor†,
- Jeffrey V. Ravetch‡,
- Kayo Inaba§, and
- Ralph M. Steinman*,¶
- *Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, and
- ‡Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021;
- †Division of Plastic and Reconstructive Surgery, New York Presbyterian Hospital–Weill Cornell Medical Center, New York, NY 10021; and
- §Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
-
Contributed by Ralph M. Steinman, December 28, 2005
Abstract
Thymic-derived CD25+ CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we evaluated the ability of dendritic cells (DCs) to expand alloantigen-specific Tregs in the mixed leukocyte reaction (MLR) that develops from polyclonal populations of T cells. The allogeneic DCs, when supplemented with IL-2 in the cultures, were much more effective than bulk spleen cells in expanding the numbers of Tregs. Likewise, DCs and not spleen cells were effective in sustaining expression of the transcription factor Foxp3 in Tregs, but neither IL-2 nor CD80/86 was required for this effect in the cultures. On a per-cell basis, the DC-expanded, but not unexpanded, Tregs were more potent suppressors of a fresh MLR by CD25− CD4+ T cells. Suppression was 3- to 10-fold more active for MLRs induced by the original alloantigens than for third-party stimulators. When DC-expanded Tregs were introduced into sublethally irradiated hosts, the T cells suppressed graft-versus-host-disease induced by CD25− CD4+ T cells. Again, suppression was more active against the same mouse strain that provided the DCs to expand the Tregs. Therefore, alloantigen-selected Tregs are more effective suppressors of responses to major transplantation antigens, and these Tregs can be expanded from a polyclonal repertoire by DCs.
Footnotes
- ¶To whom correspondence should be addressed. E-mail: steinma{at}rockefeller.edu
-
Author contributions: S.Y., K.I., and R.M.S. designed research; S.Y., M. Patel, A.H., A.B., and M. Pack performed research; H.F., K.V.T., M.T., and J.V.R. contributed new reagents/analytic tools; S.Y., K.I., and R.M.S. analyzed data; and S.Y. and R.M.S. wrote the paper.
-
Conflict of interest statement: No conflicts declared.
- Abbreviations:
- Tregs,
- CD25+ CD4+ regulatory T cells;
- MLR,
- mixed leukocyte reaction;
- DCs,
- dendritic cells;
- BM-DCs,
- bone marrow-derived DCs;
- APCs,
- antigen-presenting cells;
- CFSE,
- carboxyfluorescein diacetate succinimidyl ester;
- GVHD,
- graft-versus-host disease.
- © 2006 by The National Academy of Sciences of the USA
