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International Immunology Advance Access originally published online on November 1, 2004
International Immunology 2004 16(12):1769-1780; doi:10.1093/intimm/dxh178
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© 2004 The Japanese Society for Immunology

Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells

Zoltán Fehérvári1 and Shimon Sakaguchi1,2,3

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Shogo-in 53, Sakyo-ku, Kyoto 606-8507, Japan
2 Laboratory of Immunopathology, Research Center for Allergy and Immunology, The Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan
3 Core Research for Evolutional Science and Technology (CREST) Program, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to: Z. Fehervari; E-mail: zed72{at}frontier.kyoto-u.ac.jp

Naturally occurring CD4+CD25+ regulatory T (TR) cells play crucial roles in normal immunohomeostasis. CD4+CD25+ TR cells exhibit a number of interesting in vitro properties including a ‘default state’ of profound anergy refractory to conventional T cell stimuli. We investigated the in vitro activation requirements of CD4+CD25+ TR cells using bone marrow-derived DC, which as professional antigen presenting cells (APC) can support the activation of normal naïve T cells. Comparison of different APC types revealed that LPS-matured DC were by far the most effective at breaking CD4+CD25+ TR cell anergy and triggering proliferation, and importantly their IL-2 production. Examination of Foxp3, a key control gene for CD4+CD25+ TR cells, showed this to be stably expressed even during active proliferation. Although CD4+CD25+ TR cell proliferation was equivalent to that of CD25– cells their IL-2 production was considerably less. Use of IL-2–/– mice demonstrated that the DC stimulatory ability was not dependent on IL-2 production; nor did IL-15 appear crucial but was, at least in part, related to costimulation. DC also blocked normal CD4+CD25+ TR cell-mediated suppression partially via IL-6 secretion. DC therefore possess novel mechanisms to control the suppressive ability, expansion and/or differentiation of CD4+CD25+ TR cells in vivo.

Keywords: anergy, CD25+CD4+ TR, DC, LPS, regulation

Transmitting editor: A. Cooke


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