Compelling evidence suggests that Foxp3 + CD25 + CD4 + Treg play a fundamental role in immunoregulation. We have previously demonstrated that Treg have to enter peripheral tissues to suppress ongoing inflammation. However, relatively little is known about how Treg acquire the expression of homing receptors required for tissue-or inflammationspecific migration. Migratory properties of conventional naïve T cells are shaped by the tissue microenvironment and organ-specific dendritic cells during priming. Here, we show that this basic concept also holds true for CD25 + CD4 + Treg: Priming of Treg within peripheral LN led to the expression of selectin ligands, which facilitate migration into inflamed skin, whereas activation within mesenteric LN led to induction of the integrin a 4 b 7 , which is required for migration into mucosal tissues. Furthermore, we could establish in vitro culture systems containing either dendritic cells from mesenteric and peripheral LN, or retinoic acid and IL-12 as polarizing compounds to induce mucosa-and skin-seeking Treg, respectively. Together, our results demonstrate that Treg, similarly to conventional T cells, can be configured with organ-selective homing properties allowing efficient targeting into distinct tissues.
IntroductionMigration of T cell subsets to different tissues is determined by the combined expression of adhesion molecules and chemokine receptors (CCR) on the cell surfaces [1][2][3][4]. Among these homing receptors (HR), the integrin a 4 b 7 [5,6] and the chemokine receptor CCR9 [7][8][9] mediate the homing of T cell subsets to GALT such as mesenteric LN (mLN) and Peyer's patches (PP) and to the small intestinal lamina propria and the mucosal epithelium. In contrast, T cell trafficking to the skin is mediated by P-(P-lig) and E-(E-lig) selectin ligands [10,11] as well as .Recently, a number of studies have described that antigen-dependent differentiation of naïve T cells in lymphoid organs leads to the generation of effector T cells exhibiting a capacity to enter peripheral extralymphoid tissues [2]. Effector T cells generated in different lymphoid organs display distinct tissue tropism, which is regulated by an organ-specific induction of adhesion molecules and chemokine receptors during T cell priming [4,[15][16][17][18][19][20][21]. For example, T cells activated in mLN and PP draining the gut acquire high levels of the integrin a 4 b 7 , whereas activation in skin-draining peripheral LN (pLN) results in the upregulation of selectin ligands such as P-lig. Tissuespecific DC have been shown in a number of in vitro and in vivo studies to be involved in the instruction of naïve T cells [4,[17][18][19][20][22][23][24] reported that GALT DC were capable of converting metabolites of dietary vitamin A into retinoic acid (RA), which in turn induced T cell expression of a 4 b 7 and CCR9, leading to the generation of gut-tropic T cells. However, the factors, which are involved in the generation of skin-specific T cell homing in vivo, are largely unknown, although important ...