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Experience-Driven Development: Effector/Memory-Like _E⁺Foxp3⁺ Regulatory T Cells Originate from Both Naive T Cells and Naturally Occurring Naive-Like Regulatory T Cells¹

Christiane Siewert^*, Uta Lauer^*, Sascha Cording^*, Tobias Bopp, Edgar Schmitt, Alf Hamann^* and Jochen Huehn^2,*

^* Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Campus Mitte, Berlin; and Institut fuer Immunologie, Johannes-Gutenberg-Universitaet, Mainz, Germany

Naturally occurring Foxp3⁺CD25⁺CD4⁺ regulatory T cells (Treg) have initially been described as anergic cells; however, more recent in vivo studies suggest that Tregs vigorously proliferate under both homeostatic as well as inflammatory conditions. We have previously identified a subset of murine CD4⁺ Tregs, which is characterized by expression of the integrin _Eβ₇ and which displays an effector/memory-like phenotype indicative of Ag-specific expansion and differentiation. In the present study, the _E⁺ Treg subset was found to contain a large fraction of cycling cells under homeostatic conditions in healthy mice. Using an adoptive transfer system of Ag-specific T cells, we could demonstrate that the vast majority of transferred natural, naive-like CD25⁺CD4⁺ Tregs acquired expression of the integrin _Eβ₇ upon tolerogenic application of Ag via the oral route. In addition, using the same system, Foxp3⁺ Tregs could be de novo induced from conventional naive CD25^–CD4⁺ T cells, and this conversion was associated with concomitant expression of _E. These findings suggest that Tregs expressing the integrin _E are effector/memory Tregs with a high turnover rate that can develop in the periphery upon Ag contact under tolerogenic conditions, both from thymic-derived CD25⁺CD4⁺ Tregs with a naive-like phenotype as well as from conventional naive T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants SFB 633 and SFB 650 from the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Jochen Huehn, Experimentelle Rheumatologie, Charité Universitaetsmedizin Berlin, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail address: Huehn{at}drfz.de

³ Abbreviations used in this paper: Tregs, regulatory T cells; LN, lymph node; d3Tx, day 3 thymectomized; livLN, liver-draining lymph node; mLN, mesenteric lymph node; PP, Peyer’s Patch.

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