International Immunology Advance Access originally published online on July 5, 2004
International Immunology 2004 16(8):1189-1201; doi:10.1093/intimm/dxh122
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© 2004 The Japanese Society for Immunology
ORIGINAL RESEARCH PAPERS |
Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells
1 Department of Experimental Pathology, Institute for Frontier Medical Sciences and 2 Department of Transplantation and Immunology, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
3 Laboratory of Immunopathology, Research Center for Allergy and Immunology, Institute for Physical and Chemical Research, Yokohama 230-0045, Japan
4 Core Research for Evolutional Science and Technology (CREST) Program, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
5 Present address: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo 153-8904, Japan
Correspondence to: S. Sakaguchi; E-mail: shimon{at}frontier.kyoto-u.ac.jp
Naturally arising CD25+CD4+ regulatory T (TR) cells can be exploited to establish immunologic tolerance to non-self antigens. In vivo exposure of CD25+CD4+ T cells from normal naive mice to alloantigen in a T cell-deficient environment elicited spontaneous expansion of alloantigen-specific CD25+CD4+ TR cells, which suppressed allograft rejection mediated by subsequently transferred naive T cells, leading to long-term graft tolerance. The expanded TR cells, which became CD25low in the absence of other T cells, stably sustained suppressive activity, maintained expression levels of other TR cell-associated molecules, including Foxp3, CTLA-4 and GITR, and could adoptively transfer tolerance to normal mice. Furthermore, specific removal of the TR cells derived from originally transferred CD25+CD4+ TR cells evoked graft rejection in the long-term tolerant mice, indicating that any TR cells deriving from CD25–CD4+ naive T cells minimally contribute to graft tolerance and that natural TR cells are unable to infectiously confer significant suppressive activity to other T cells. Similar antigen-specific expansion of TR cells can also be achieved in vitro by stimulating naturally present CD25+CD4+ T cells with alloantigen in the presence of IL-2. The expanded CD25+CD4+ T cells potently suppressed even secondary MLR in vitro and, by in vivo transfer, established antigen-specific long-term graft tolerance. Thus, in vivo or in vitro, direct or indirect ways of antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ TR cells can establish antigen-specific dominant tolerance to non-self antigens, and would also be instrumental in re-establishing self-tolerance in autoimmune disease and antigen-specific negative control of pathological immune responses.
Keywords: CTLA-4, GITR, transplantation tolerance
Transmitting editor: K. Okumura
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