Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Zabel, Brian A.; Agace, William W.; Campbell, James J.; Heath, Heidi; Parent, David W; Roberts, Arthur I.; Ebert, Ellen C.; Kassam, Nasim; Qin, Shixin; Zovko, Maria; LaRosa, Gregory J.; Yang, Lili; Soler, Dulce; Butcher, Eugene C.; Ponath, Paul D.; Parker, Christina M.; Andrew, David P.

doi:10.1084/jem.190.9.1241

Cited by 449 publications

(418 citation statements)

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(47 reference statements)

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“…Interestingly, we observed that SEA pre-treated mice had an increased expression of the chemokine receptor CCR9 on their Treg population in MLN at 6 wk of age. Expression of CCR9 is imprinted on T cells primed in the Peyer's patches and the gut draining MLN, enabling migration to the gut [41][42][43]. This finding implies that the observed improvement in oral tolerance might be due to an increased recruitment of Treg to the gut.…”

Section: Discussionmentioning

confidence: 96%

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

et al. 2009

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The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.Key words: Allergic sensitisation . Mucosal immunity . Staphylococcal enterotoxin A . Tolerance Supporting Information available online IntroductionAllergies have increased markedly in Western industrialised countries, where they now afflict every third child. Allergies are linked to wealth, good education and small families, observations that have given rise to the hygiene hypothesis, according to which the developing immune system should be exposed to appropriate microbial stimulation in early childhood in order to mature correctly and for allergies to be avoided [1,2]. The hygiene hypothesis is also supported by experimental data. Germ-free animals are less prone to develop oral Ã These author contributed equally to this work. Eur. J. Immunol. 2009. 39: 447-456 DOI 10.1002 Immunomodulation 447 tolerance than animals reared conventionally [3,4]. Oral tolerance is induced by passage of antigens over the gut mucosa, prevents against both Th1-and Th2-dominated immune responses [5] and includes development of Treg [6,7]. Natural thymic-dependent Treg (CD4 1 CD25 hi FoxP3 1 ) are fundamental in protection against autoimmunity, gut inflammation and IgE responses. This cell subset has reduced functional capacity in germ-free animals [8].The strongest T-cell activators known are the ''superantigens'', exotoxins produced by certain pathogenic bacteria such as Staphylococcus aureus. These include staphylococcal enterotoxin A, B, C, D and E, as well as toxic shock syndrome toxin-1. The superantigen binds to the variable part of the TCR and to the MHC class II molecule, thereby ''mimicking'' antigen recognition, which leads to T-cell activation [9][10][11][12]. As many as 10-30% of all T cells can become activated by a certain superantigen compared with o0...

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Section: Discussionmentioning

confidence: 96%

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

et al. 2009

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“…Constitutively expressed chemokines act in primary and secondary lymphoid organs [16,17,26] and peripheral tissues [27,28]. The CCR7 ligands, CCL19 and CCL21 [29,30], are expressed in the T-cell area of secondary lymphoid organs as well as on high endothelial venules (HEV) [31] and orchestrate the migration of CCR7 1 cells.…”

Section: Introductionmentioning

confidence: 99%

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking. Monocytes can integrate stimuli provided by inflammatory chemokines in the presence of homeostatic chemokines. In particular, migration and cell responses could occur at much lower concentrations of the CCR2 agonists, in the presence of chemokines (CCL19 and CCL21) that per se do not act on monocytes. Binding studies on CCR2 1 cells showed that CCL19 and CCL21 do not compete with the CCR2 agonist CCL2. Furthermore, the presence of CCL19 or CCL21 could influence the degradation of CCL2 and CCL7 on cells expressing the decoy receptor D6. These findings disclose a new scenario to further comprehend the complexity of chemokinebased monocyte trafficking in a vast variety of human inflammatory disorders.Key words: Chemokine receptors . Chemokines . Monocytes . Synergism IntroductionConcomitant exposure to multiple chemokines, the key controllers of several immune cell functions [1], can result in enhancement of immune responses. Only recently, a broad phenomenon known as ''chemokine synergism'' has been identified [2][3][4][5][6][7][8][9][10]. Cells expressing two or more chemokine receptors, in the presence of the selective agonists, can amplify their response [2][3][4][5][6]11]. The responses mediated by low agonist concentrations can be powerfully enhanced by non-ligand chemokines in cells that do not bear the second chemokine receptor [7][8][9]. Using different biochemical approaches, these studies demonstrated that CC and CXC chemokines form heteromeric complexes, which could endow the agonist with higher activity [7,9,12].Chemokines mediate their effects through interactions with heterotrimeric G-protein-coupled receptors [13][14][15]. Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25]. Therefore, there are strong indications that a cell needs to 1118integrate more than one signal provided by its environment and that environmental factors other than agonists might influence their responses.Chemokine production can be either constitutive or triggere...

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“…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 CCR4 and CCR10 [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

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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Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Cited by 449 publications

References 45 publications

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Induction of organ‐selective CD4⁺ regulatory T cell homing

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Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Cited by 449 publications

References 45 publications

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Induction of organ‐selective CD4+ regulatory T cell homing

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Induction of organ‐selective CD4⁺ regulatory T cell homing