Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

Kunkel, Eric J.; Campbell, James J.; Haraldsen, Guttorm; Pan, Junliang; Boisvert, Judie; Roberts, Arthur I.; Ebert, Ellen C.; Vierra, Mark A.; Goodman, Stuart B.; Genovese, Mark C.; Wardlaw, Andrew J.; Greenberg, Harry B.; Parker, Christina M.; Butcher, Eugene C.; Andrew, David P.; Agace, William W.

doi:10.1084/jem.192.5.761

Cited by 586 publications

(487 citation statements)

References 16 publications

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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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“…In contrast, in the intestine, mucosal addressin cell adhesion molecule-1 is expressed on postcapillary venules in the intestinal lamina propria where T cells that highly express ␣ 4 ␤ 7 integrin are migrated. Furthermore, these T cells express CCR9, which is the specific receptor for the chemokine thymus-expressed chemokine, that are expressed by small intestinal epithelium (29).…”

Section: Discussionmentioning

confidence: 99%

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

Tsumori

Kohrogi

Goto

et al. 2003

The Journal of Immunology

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T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-γ mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

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Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

Cited by 586 publications

References 16 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

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

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Lymphocyte Cc Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (Teck) Expression Distinguish the Small Intestinal Immune Compartment

Cited by 586 publications

References 16 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

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

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Induction of organ‐selective CD4⁺ regulatory T cell homing

Induction of organ‐selective CD4⁺ regulatory T cell homing