Skin‐versus gut‐skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4<sup>+</sup>CD25<sup>+</sup> suppressor T cells

Iellem, Andrea; Colantonio, Lucia; D’Ambrosio, Daniele

doi:10.1002/eji.200323658

Cited by 100 publications

(88 citation statements)

References 39 publications

(43 reference statements)

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“…Whereas CCR7-deficient naive-like Treg fail to recirculate through LN, resulting in an almost complete abolishment of their ability to inhibit the proliferation of naive T cells at this site, effector/memory-like Treg from CCR7 -/-mice display an increased accumulation in inflamed sites, which was accompanied by an enhanced suppression of the inflammatory reaction. CCR7 expression was predominantly observed on naive-like Treg [3,5,6,11,[31][32][33][34] and CCR7-expressing CD62L high CD25 + CD4 + Treg were found to be very efficient in preventing the development of autoimmunity [5] or in suppressing graft-versus-host disease [35,36]. It was suggested that Treg recirculation through LN mediated by CCR7 and CD62L is a prerequisite to suppress priming of autoreactive effector cells.…”

Section: Discussionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Foxp3 + CD25 + CD4 + Treg play a fundamental role in the maintenance of self tolerance and the control of inflammatory reactions. Previous data demonstrated a division of labor between naive-and effector/memory-like Treg subsets, which is largely based on their lymph node-recirculating and inflammation-seeking migration behavior, respectively. The chemokine receptor CCR7 is expressed on both types of Treg subsets, albeit at different levels. Whether it fulfills similar or distinct roles in these subsets has not been studied so far. We here show that the recirculation of naive-like Treg through LN and, to some extent, the gut is dependent on CCR7. Lack of CCR7 not only prevents recirculation, but also almost completely abolishes the ability of naive-like Treg to control the priming phase of an immune response. In contrast, CCR7 deficiency in effector/memory-like Treg promotes their accumulation in inflamed sites, compatible with a role of CCR7 for exit from the tissue. Local Treg accumulation was accompanied by an enhanced suppression of inflammation. Together, our findings provide conclusive evidence that CCR7 expression on Treg differentially controls in vivo function of the naive-and effector/memory-like subsets.

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Section: Discussionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Section: Introductionmentioning

confidence: 99%

“…Treg are by no means homogeneous, but rather can be subdivided into naïve-like subsets, which preferentially recirculate through lymphoid tissues, and effector/memory subsets, which efficiently migrate into peripheral sites and sites of ongoing immune responses [30][31][32][33]. Thus, it is not surprising that Treg display a high HR versatility [31,[34][35][36][37][38][39].A few studies have demonstrated the capacity of Treg to down-regulate established immune reactions [31,[40][41][42], and, therefore, it has been suggested that regulation might act locally in the inflammatory environment. Indeed, we and others have recently demonstrated that expression of certain HR such as selectin ligands and chemokine receptors on Treg subsets critically influences their suppressive capacity in vivo [43][44][45][46], suggesting that appropriate localization is indispensable for Treg function [30].…”

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confidence: 99%

Induction of organ‐selective CD4⁺ regulatory T cell homing

et al. 2007

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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 ...

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“…This combination should allow Treg to enter from blood into secondary lymphoid tissues, suggesting a role for Treg in controlling systemic immunity as central memory T cells (14) at secondary lymphoid organs. In contrast, it has also been reported that unfractionated blood CD4 ϩ CD25 ϩ T cells express variable levels of peripheral tissue-homing receptors such as skin-associated CLA (4,15), CCR4 (16), and gut-associated ␣ 4 ␤ 7 integrin (17). In addition, Iellem et al (15) reported Treg express skin-vs gut-skewed homing receptors, describing that ϳ30% of CD4 ϩ CD25 ϩ T cells express CLA.…”

mentioning

confidence: 99%

“…In contrast, it has also been reported that unfractionated blood CD4 ϩ CD25 ϩ T cells express variable levels of peripheral tissue-homing receptors such as skin-associated CLA (4,15), CCR4 (16), and gut-associated ␣ 4 ␤ 7 integrin (17). In addition, Iellem et al (15) reported Treg express skin-vs gut-skewed homing receptors, describing that ϳ30% of CD4 ϩ CD25 ϩ T cells express CLA. However, the peripheral tissue-homing specificity of the true CD4 ϩ CD25 high Treg remains obscure.…”

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confidence: 99%

The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors

Hirahara

Liu

Clark

et al. 2006

The Journal of Immunology

249

219

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CD4+CD25+ T regulatory cells (Treg) are thought to be important in the peripheral tolerance. Recent evidence suggests that human peripheral blood CD4+CD25+ T cells are heterogeneous and contain both CD4+CD25high T cells with potent regulatory activity and many more CD4+CD25low/med nonregulatory T cells. In this study, we found that virtually all peripheral blood CD4+CD25highFoxp3+ Treg expressed high levels of the chemokine receptor CCR4. In addition, 80% of Treg expressed cutaneous lymphocyte Ag (CLA) and 73% expressed CCR6. These molecules were functional, as CLA+ Treg showed CD62E ligand activity and demonstrable chemotactic responses to the CCR4 ligands CCL22 and CCL17 and to the CCR6 ligand CCL20. The phenotype and chemotactic response of these Treg were significantly different from those of CD4+CD25med nonregulatory T cells. We further demonstrated that blood CLA+ Treg inhibited CD4+CD25− T cell proliferation induced by anti-CD3. Based on homing receptor profile, CLA+ Treg should enter normal skin. We next isolated CD4+CD25high T cells directly from normal human skin; these cells suppressed proliferation of skin CD4+CD25− T cells. Therefore, the majority of true circulating Treg express functional skin-homing receptors, and human Treg may regulate local immune responses in normal human skin.

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Skin‐versus gut‐skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4⁺CD25⁺ suppressor T cells

Cited by 100 publications

References 39 publications

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Induction of organ‐selective CD4⁺ regulatory T cell homing

The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors

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Skin‐versus gut‐skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4+CD25+ suppressor T cells

Cited by 100 publications

References 39 publications

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Induction of organ‐selective CD4+ regulatory T cell homing

The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors

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Skin‐versus gut‐skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4⁺CD25⁺ suppressor T cells

Induction of organ‐selective CD4⁺ regulatory T cell homing