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Immune System the Regional Specialization of the Mucosal And The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System This information is current as of September 25, 2021. Konstantinos A. Papadakis, John Prehn, Viera Nelson, Lorna Cheng, Scott W. Binder, Paul D. Ponath, David P. Andrew and Stephan R. Targan J Immunol 2000; 165:5069-5076; ; doi: 10.4049/jimmunol.165.9.5069 Downloaded from http://www.jimmunol.org/content/165/9/5069 References This article cites 45 articles, 22 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/165/9/5069.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Role of Thymus-Expressed Chemokine and Its Receptor CCR9 on Lymphocytes in the Regional Specialization of the Mucosal Immune System1 Konstantinos A. Papadakis,2* John Prehn,* Viera Nelson,† Lorna Cheng,† Scott W. Binder,† Paul D. Ponath,‡ David P. Andrew,‡ and Stephan R. Targan* Chemokines play an important role in the migration of leukocytes at sites of inflammation, and some constitutively expressed chemokines may direct lymphocyte trafficking within lymphoid organs and peripheral tissues. Thymus-expressed chemokine (TECK or Ck␤-15/CCL25), which signals through the chemokine receptor CCR9, is constitutively expressed in the thymus and ␣ ␤ small intestine but not colon, and chemoattracts a small fraction of PBLs that coexpress the integrin 4 7. Here we show that TECK is expressed in the human small bowel but not colon by endothelial cells and a subset of cells in intestinal crypts and lamina Downloaded from propria. CCR9 is expressed in the majority of freshly isolated small bowel lamina propria mononuclear cells (LPMC) and at significantly higher levels compared with colonic LPMC or PBL. TECK was selectively chemotactic for small bowel but not colonic LPMC in vitro. The TECK-induced chemotaxis was sensitive to pertussis toxin and partially inhibited by Abs to CCR9. TECK attracts predominantly the T cell fraction of small bowel LPMC, whereas sorted CD3؉CCR9؉ and CD3؉CCR9؊ lymphocytes produce similar Th1 or Th2 cytokines at the single cell level. Collectively, our data suggest that the selective expression of TECK ؉ in the small bowel underlie the homing of CCR9 intestinal memory T cells to the small bowel rather than to the colon. This http://www.jimmunol.org/ regional specialization implies a segregation of small intestinal from colonic immune responses. The Journal of Immunology, 2000, 165: 5069–5076. hemokines (chemotactic cytokines) are small, 6- to 14- chemokine 1, and CCR9, which binds thymus-expressed chemokine kDa heparin-binding proteins, which play a role in a variety (TECK) only, among others (5–15). Chemokines were identified by C of biological processes, most notably leukocyte chemotaxis their ability to direct extravasation of inflammatory cells during in- (1–3). They are classified as C, CC, CXC, and CX3C based on the fection (1, 2). However, recent data identified several chemokines that positioning of cysteine residues that form two disulfide bonds (3). are expressed constitutively in lymphoid and extra-lymphoid tissues, by guest on September 25, 2021 Chemokines mediate their effects through G protein-coupled seven indicating that these chemokines might have homeostatic function by transmembrane domain receptors, which are currently divided into regulating lymphocyte trafficking to or within lymphoid organs and in four families based on the type of chemokine that they bind; they are peripheral tissues (3, 16–21). Certain chemokines, such as stromal CXCR1 to CXCR5, and CCR1 to CCR9, XCR1, or CX3CR1 (3). cell-derived factor 1 (SDF-1), 6-C-kine, and MIP-3␤ can also stim- Most chemokines recognize several receptors, and a single receptor ulate leukocyte adhesion and arrest on endothelium by triggering in- can bind more than one chemokine (4). However, some receptors bind tegrin activation (22, 23). It is thought that the combined expression a single chemokine such as CCR6, which binds macrophage inflam- of adhesion molecules and chemokine receptors on the cell surface 3 ␣ matory protein (MIP) -3 , CXCR5, which binds B cell-attracting provide an “address code” for leukocyte migration to different sites (24). In contrast to naive T cells, memory/effector cells migrate *Department of Medicine, Division of Gastroenterology and Inflammatory Bowel mostly through peripheral tissues, and this process is controlled by Disease Center, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA 90048; †Department of Pathology and Labo- the expression of different sets of integrins and chemokine recep- ratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and ‡Leu- tors (25–28). Thus, naive T cells express CXCR4, the receptor for koSite, Cambridge, MA 02142 SDF-1, and CCR7, the receptor for EBV-induced molecule 1 li- 1 This work was supported by National Institutes of Health Grants DK-46763 and DK-56328. gand chemokine and secondary lymphoid tissue chemokine (also Received for publication May 22, 2000. Accepted for publication July 31, 2000. called 6-C-kine). Mice deficient in CCR7 or secondary lymphoid tissue chemokine have defective homing of naive T cells to sec- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance ondary lymphoid organs (16, 29). Gene knockout studies have es- with 18 U.S.C. Section 1734 solely to indicate this fact. tablished that CXCR5 is required for B cell migration to B cell 2 Address correspondence and reprint requests to Dr. Konstantinos A. Papadakis, follicles of spleen and Peyer’s patches (PP; Ref. 30). In addition, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4062, Los Angeles, CA 90048. E-mail address: [email protected] the defects in lymph node (LN) development observed in lympho- or Dr. Stephan R. Targan, Inflammatory Bowel Disease Center, Cedars-Sinai Medical toxin-␣ and TNF knockout mice have been attributed, at least in Center, 8700 Beverly Boulevard, D-4063, Los Angeles, CA 90048. E-mail address: part, to decreased production of chemokines by stromal LN cells [email protected] (31). Collectively, these data suggest an important role of certain 3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; LN, lymph node; LPMC, lamina propria mononuclear cells; PP, Peyer’s patches; TECK, chemokines in regulating the homing of specific T cell subsets and thymus-expressed chemokine; hTECK, human TECK; IECs, intestinal epithelial other immune cells into microanatomic compartments of second- cells; MAdCAM-1, mucosal addressin cell-adhesion molecule; mTECK, murine TECK; IELs, intraepithelial lymphocytes; SDF-1, stromal cell-derived factor 1; MLN, ary lymphoid organs. Certain chemokine receptors are also pref- mesenteric lymph node; MFI, mean fluorescence intensity. erentially expressed on naive T cells under Th1 or Th2 polarizing Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 5070 CCR9-POSITIVE T CELLS/TECK EXPRESSION IN HUMAN SMALL BOWEL IMMUNITY conditions in vitro. Th1 cells predominantly express CXCR3 and After washing twice, cells were resuspended in 400 ␮l of 1% paraformal- CCR5 (32–36). In contrast, Th2 cells express CCR3, CCR4, and dehyde in PBS and analyzed by FACS (Becton Dickinson, Mountain View, 4 CCR8 (3, 24, 32, 33, 35, 36). Recently, the orphan chemokine CA). Events (10 ) were routinely collected and analyzed using Lysis II software (Becton Dickinson Immunocytometry Systems, San Jose, CA). receptor GPR-9-6, now designated CCR9, was found to be ex- Both the percentage of positive cells and the mean fluorescence intensity pressed on a small percentage (2–4%) of circulating memory T (MFI) of the cells were determined. ␣ ␤ cells, all of which express the mucosal homing ligand 4 7 (9). The ligand for CCR9, TECK, also CCL25/Ck␤-15 according to RT-PCR the recent chemokine/chemokine receptor nomenclature (3), is se- Total RNA was extracted from small bowel or colonic intestinal mucosa lectively expressed in the thymus and small intestine (9, 13, 37, and freshly isolated small bowel or colonic IECs and LPMC using the 38). In addition, CCR9 mRNA is expressed in the thymus, small RNeasy Kit as recommended by the manufacturer (Qiagen, Valencia, CA). One microgram of RNA was reverse-transcribed into cDNA with oligo(dT) intestine, and at lower levels in the spleen, suggesting that the in a 20-␮l volume using a Thermoscript RT-PCR System (Life Technol- CC-chemokine TECK and its receptor, CCR9, may play an im- ogies, Grand Island, NY) according to a standard protocol. Primers were portant role in T cell maturation and in the intestinal immune re- designed as described elsewhere (9). Primers for TECK were: sense 5Ј- sponse (9). TCGAAGAAGCTTATGAACCTGTGGCTCCTG-3Ј antisense 5Ј-AA Ј The potential importance of CCR9 and TECK in mucosal im- GAAGTCTAGATCACAGTCCTGAATTAGC-3 (product 453 bp). Two microliters of the reaction cDNA was mixed with 10 mM dNTP, 10 ␮M munity prompted us to study the expression of this chemokine/ ␮ primers, 50 mM MgCl2,and5U/ l of Platinum Taq DNA polymerase in chemokine receptor pair in the normal small and large bowel.
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