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CD25⁺CD4⁺ Regulatory T Cell Migration Requires L-Selectin Expression: L-Selectin Transcriptional Regulation Balances Constitutive Receptor Turnover¹

Guglielmo M. Venturi^*, Rochelle M. Conway, Douglas A. Steeber and Thomas F. Tedder^2,*

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; and Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53201

The molecular mechanisms controlling regulatory CD25⁺Foxp3⁺CD4⁺ T cell (T_reg) migration are central to in vivo immune responses. T_reg cell subsets differentially express L-selectin, an adhesion molecule mediating lymphocyte migration to peripheral LNs (PLNs) and leukocyte rolling during inflammation. In this study, L-selectin was essential for T_reg cell migration and normal tissue distribution. Specifically, there was a 90% reduction in PLN T_reg cells in L-selectin^–/– mice with a compensatory increase in spleen T_reg cell numbers. Unexpectedly, however, 40% of the CD4⁺ T cells remaining within PLNs of L-selectin^–/– mice were T_reg cells. The migratory properties of T_reg cells were nonetheless markedly different from those of naive CD4⁺ T cells, with 3- to 9-fold lower migration of T_reg cells into PLNs and 2-fold lower migration into the spleen. T_reg cells also turned over cell surface L-selectin at a faster rate than CD25^–CD4⁺ T cells, but maintained physiologically appropriate L-selectin densities for optimal migration. Specifically, T_reg cells expressed 30–40% more cell surface L-selectin when its endoproteolytic cleavage was blocked genetically, which resulted in a 2-fold increase in T_reg cell migration into PLNs. However, increased L-selectin cleavage by T_reg cells in wild-type mice was accompanied by 2-fold higher L-selectin mRNA levels, which resulted in equivalent cell surface L-selectin densities on T_reg and naive T cells. Thus, T_reg cells and CD25^–CD4⁺ T cells share similar requirements for L-selectin expression during migration, although additional molecular mechanisms constrain T_reg cell migration beyond what is required for naive CD4⁺ T cell migration.

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 National Institutes of Health Grants CA96547, CA105001, CA098492, and AI56363, and a Basic Immunology Training Grant T32 A1052077 (to G.M.V.).

² Address correspondence and reprint requests to Dr. Thomas F. Tedder, Box 3010, Department of Immunology, Room 353, Jones Building, Research Drive, Duke University Medical Center, Durham, NC 27710. E-mail address: thomas.tedder{at}duke.edu

³ Abbreviations used in this paper: T_reg, CD25⁺CD4⁺ regulatory T cell; LN, lymph node; PLN, peripheral LN; MLN, mesenteric LN.

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