PT  - JOURNAL ARTICLE
AU  - Skapenko, Alla
AU  - Kalden, Joachim R.
AU  - Lipsky, Peter E.
AU  - Schulze-Koops, Hendrik
TI  - The IL-4 Receptor α-Chain-Binding Cytokines, IL-4 and IL-13, Induce Forkhead Box P3-Expressing CD25<sup>+</sup>CD4<sup>+</sup> Regulatory T Cells from CD25<sup>−</sup>CD4<sup>+</sup> Precursors
AID  - 10.4049/jimmunol.175.9.6107
DP  - 2005 Nov 01
TA  - The Journal of Immunology
PG  - 6107--6116
VI  - 175
IP  - 9
4099  - http://www.jimmunol.org/content/175/9/6107.short
4100  - http://www.jimmunol.org/content/175/9/6107.full
SO  - J. Immunol.2005 Nov 01; 175
AB  - The mechanisms underlying the extrathymic generation of CD25+CD4 regulatory T cells (Tregs) are largely unknown. In this study the IL-4R α-chain-binding cytokines, IL-4 and IL-13, were identified as inducers of CD25+ Tregs from peripheral CD25−CD4 naive T cells. IL-4-induced CD25+ Tregs phenotypically and functionally resemble naturally occurring Tregs in that they are anergic to mitogenic stimulation, inhibit the proliferation of autologous responder T cells, express high levels of the Forkhead box P3 and the surface receptors glucocorticoid-induced TNFR family-related protein and CTLA-4, and inhibit effector T cells in a contact-dependent, but cytokine-independent, manner. The IL-4-induced generation of peripheral Tregs was independent of the presence of TGF-β or IL-10, but was dependent on Ag-specific stimulation and B7 costimulation. The significance of the IL-4Rα-binding cytokines in the generation of Ag-specific Tregs was emphasized in a mouse model of oral tolerance, in which neutralization of IL-4 and IL-13 in mice transgenic for the TCR specific for OVA completely inhibited the expansion of OVA-specific Tregs that can be induced in untreated mice by feeding the nominal Ag. Together, our results demonstrate that IL-4 and IL-13 play an important role in generating Forkhead box P3-expressing CD25+ Tregs extrathymically in an Ag-dependent manner and therefore provide an intriguing link between the well-established immunoregulatory capacity of Th2 cells and the powerful CD25+ Treg population. Moreover, our findings might provide the basis for the design of novel therapeutic approaches for targeted immunotherapy with Tregs to known Ags in autoimmune diseases or graft-vs-host reactions.