The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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Published 7 March 2005. doi:10.1084/jem.20041982
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 723-735
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ARTICLE

 Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization

Ruka Setoguchi1, Shohei Hori2, Takeshi Takahashi1, and Shimon Sakaguchi1,2,3

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
2 Research Center for Allergy and Immunology, Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan
3 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

CORRESPONDENCE Shimon Sakaguchi: shimon{at}frontier.kyoto-u.ac.jp

Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25+ CD4+ T cells, but not CD25– CD4+ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25+ CD4+ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25low CD4+ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25+ CD4+ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4+ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

Abbreviations used: BrdU, 5-bromo-29-deoxyuridine; CFSE, 5- and 6-carboxyfluorescein diacetate succinimidyl ester; EAE, experimental allergic encephalitis; NOD, nonobese diabetic; T1D, type 1 diabetes; T reg cell, regulatory T cell; Tx, thymectomized.


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