The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System

Papadakis, Konstantinos A.; Prehn, John; Nelson, Viera; Cheng, Lorna; Binder, Scott W.; Ponath, Paul D.; Andrew, David P.; Targan, Stephan R.

doi:10.4049/jimmunol.165.9.5069

Cited by 307 publications

(280 citation statements)

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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%

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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Section: Introductionmentioning

confidence: 99%

Induction of organ‐selective CD4⁺ regulatory T cell homing

et al. 2007

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“…Chemokines constitute a large family of small (ϳ8 -14 kDa), structurally related heparin binding proteins, which are constitutively expressed in lymphoid and extra lymphoid tissues, and play a critical role in immune homeostasis by regulating lymphocyte trafficking to or within lymphoid organs and in peripheral tissues (7)(8)(9)(10)(11)(12)(13). They are classified as C, CC, CXC, and CX3C based on the positioning of cysteine residues that form two disulfide bonds (14).…”

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confidence: 99%

“…CCL25 is selectively expressed in the thymus and small intestine but not colon (9,10). The only known receptor for CCL25, CCR9, is highly expressed on developing thymocytes and small intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (9,10,16).…”

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confidence: 99%

“…The only known receptor for CCL25, CCR9, is highly expressed on developing thymocytes and small intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (9,10,16). We and others (9,10,12) have proposed that the CCL25/CCR9 chemokine ligand receptor pair may play an important role in the regional specialization of intestinal immunity and that the coexpression of CCR9 and ␣ 4 ␤ 7 on the cell surface may provide a small intestinal "address code" for circulating intestinal memory T cells. We previously reported, that in peripheral blood (PB), CCR9 ϩ T lymphocytes were markedly elevated in patients with SB immune-mediated diseases, including CD, but not in patients with purely colonic CD, and that CCL25 expression is altered in inflamed SB but is not expressed in either normal or inflamed colon.…”

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confidence: 99%

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Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Saruta¹,

Yu²,

Avanesyan³

et al. 2007

The Journal of Immunology

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CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn’s disease (CD) and an increased frequency of CCR9+ T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9+ T cells in mucosal lymphoid tissues in CD. We show that CCR9+ T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9+ T cells isolated from CD SB lamina propria produced more IFN-γ and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-γ, but not IL-17, by CD lamina propria CCR9+ T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVβ analysis of CCR9+ T cells revealed a diverse TCRVβ repertoire among MLN CCR9+ T cells in patients with SB CD. Our data indicate that CCR9+ T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.

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“…For example, in mice only DC derived from Peyer's patches and mesenteric lymph nodes were able to induce expression of α 4 β 7 + and CCR9 + on CD8 + T cells leading to site specific homing of these effector cells to the small intestinal lamina propria [74,109]. CCR9, the receptor for the thymus-expressed chemokine (TECK, CCL 25), is expressed on effector B and T cells and mediates the selective migration of these effector cells to the small intestine in humans and mice [19,87,120]. Interestingly, CCR9 -/-knockout mice display reduced numbers of plasma cells in the small intestinal lamina propria and impaired ability to respond to oral vaccination [119].…”

Section: General Considerations For Mucosal Vaccinesmentioning

confidence: 99%

Mucosal delivery of vaccines in domestic animals

et al. 2006

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-Mucosal vaccination is proving to be one of the greatest challenges in modern vaccine development. Although highly beneficial for achieving protective immunity, the induction of mucosal immunity, especially in the gastro-intestinal tract, still remains a difficult task. As a result, only very few mucosal vaccines are commercially available for domestic animals. Here, we critically review various strategies for mucosal delivery of vaccines in domestic animals. This includes live bacterial and viral vectors, particulate delivery-systems such as polymers, alginate, polyphosphazenes, immune stimulating complex and liposomes, and receptor mediated-targeting strategies to the mucosal tissues. The most commonly used routes of immunization, strategies for delivering the antigen to the mucosal surfaces, and future prospects in the development of mucosal vaccines are discussed. mucosal / vaccine / livestock / animals / review

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The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System

Cited by 307 publications

References 48 publications

Induction of organ‐selective CD4⁺ regulatory T cell homing

Induction of organ‐selective CD4⁺ regulatory T cell homing

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Mucosal delivery of vaccines in domestic animals

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The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System

Cited by 307 publications

References 48 publications

Induction of organ‐selective CD4+ regulatory T cell homing

Induction of organ‐selective CD4+ regulatory T cell homing

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Mucosal delivery of vaccines in domestic animals

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Induction of organ‐selective CD4⁺ regulatory T cell homing

Induction of organ‐selective CD4⁺ regulatory T cell homing