Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells

• Published in: International immunology 2004-08, Vol.16 (8), p.1189-1201
• Main Authors: Nishimura, Eiji, Sakihama, Toshiko, Setoguchi, Ruka, Tanaka, Koichi, Sakaguchi, Shimon
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens - immunology; Antigens, CD; Antigens, Differentiation - immunology; APC antigen-presenting cell; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; Cell Count; Cells, Cultured; CTLA-4; CTLA-4 Antigen; CTLA-4 cytotoxic T lymphocyte-associated antigen-4; DNA-Binding Proteins - immunology; Forkhead Transcription Factors; GITR; GITR glucocorticoid-induced TNF receptor superfamily-related gene; Glucocorticoid-Induced TNFR-Related Protein; Mice; Mice, Inbred BALB C; MLR mixed lymphocyte reaction; MMC mitomycin C; MST median survival time; Receptors, Interleukin-2 - immunology; Receptors, Nerve Growth Factor - immunology; Receptors, Tumor Necrosis Factor - immunology; Skin Transplantation - immunology; transplantation tolerance; Transplantation Tolerance - immunology; Transplantation, Homologous - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxh122

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.