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Affinity-Based Selection of Regulatory T Cells Occurs Independent of Agonist-Mediated Induction of Foxp3 Expression¹

Lance M. Relland^*, Manoj K. Mishra, Dipica Haribhai^*, Brandon Edwards^*, Jennifer Ziegelbauer^* and Calvin B. Williams^2,*

^* Section of Rheumatology, and Section of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226

Natural regulatory T (nT_reg) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nT_reg TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nT_reg cell lineage specification. Foxp3 expression is an independent process that does not rely on "high affinity" binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFβ signaling, and the organization of the thymic architecture are also important. The development of nT_reg cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.

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 Grant R01 AI47154 from the National Institutes of Health, and by the D.B. and Marjorie A. Reinhart Family Foundation, the Nickolett and Montgomery Family Foundation, the Children’s Research Institute, and the Advancing a Healthier Wisconsin Program.

² Address correspondence and reprint requests to Dr. Calvin B. Williams, Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: cwilliam{at}mcw.edu

³ Abbreviations used in this paper: nT_reg, naturally occurring regulatory T; T_conv, conventional T; RTOC, reaggregate thymic organ culture; FTOC, fetal thymic organ culture; NTOC, neonatal thymic organ culture; APL, altered peptide ligand; CAb, clonotypic Ab; CCSP, Clara cell secretory protein; CD62L, L-selectin; SP, single positive; DN, double negative; DP, double positive; Hb, hemoglobin; HEL, hen egg lysozyme; mTEC, medullary thymic epithelial cell.

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The JI 2009 182: 1227-1228. [Full Text]