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FoxP3⁺ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues¹

Department of Comparative Pathobiology, Laboratory of Immunology and Hematopoiesis, Purdue Cancer Center, and Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907

Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3⁺ T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3⁺ T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4⁺ T cells as well as unique to the FoxP3⁺ cell lineage. In the thymus, precursors of FoxP3⁺ cells undergo the first trafficking receptor switch (CCR8/CCR9CXCR4CCR7), generating mostly homogeneous CD62L⁺CCR7⁺CXCR4^lowFoxP3⁺ T cells. CXCR4 expression is regained in FoxP3⁺ thymic emigrants in the periphery. Consistent with this switch, recent FoxP3⁺ thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3⁺ thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3⁺ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3⁺ and FoxP3^– T cell populations is that FoxP3⁺ T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3^– T cells, generating FoxP3⁺ T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.

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 study was supported in part by Grant AI063064 from National Institutes of Health-National Institute of Allergy and Infectious Diseases, by the American Heart Association, and by the Sidney Kimmel Foundation (to C.H.K).

² Address correspondence and reprint requests to Dr. Chang Kim, Department of Comparative Pathobiology, Purdue University, 725 Harrison Street, West Lafayette, IN 47907. E-mail address: chkim{at}purdue.edu

³ Abbreviations used in this paper: FoxP3, forkhead box P3; Treg, regulatory T cell; PLN, peripheral lymph node; MLN, mesenteric lymph node; PP, Peyer’s patch; mOVA, membrane-bound OVA; DP, double positive; SP, single positive; DN, double negative.

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