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CCL25 Mediates the Localization of Recently Activated Cd8alphabeta(+) Lymphocytes to the Small-Intestinal Mucosa

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CCL25 Mediates the Localization of Recently Activated Cd8alphabeta(+) Lymphocytes to the Small-Intestinal Mucosa CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. Svensson Frej, Marcus; Marsal, Jan; Ericsson, Anna; Carramolino, Laura; Brodén, Therese; Márquez, Gabriel; Agace, William Published in: Journal of Clinical Investigation DOI: 10.1172/JCI200215988 2002 Link to publication Citation for published version (APA): Svensson Frej, M., Marsal, J., Ericsson, A., Carramolino, L., Brodén, T., Márquez, G., & Agace, W. (2002). CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. Journal of Clinical Investigation, 110(8), 1113-1121. https://doi.org/10.1172/JCI200215988 Total number of authors: 7 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 CCL25 mediates the localization Rapid Publication of recently activated See the related Commentary beginning on page 1079. CD8αβ+ lymphocytes to the small-intestinal mucosa Marcus Svensson,1 Jan Marsal,1 Anna Ericsson,1 Laura Carramolino,2 Therese Brodén,1 Gabriel Márquez,2 and William W. Agace1 1Immunology Section, Department of Cell and Molecular Biology, Lund University, Lund, Sweden 2Departmento de Inmunología, Centro Nacional de Biotecnología, Universidad Autónoma de Madrid, Madrid, Spain The recruitment of antigen-specific T lymphocytes to the intestinal mucosa is for an involvement of chemokines central to the development of an effective mucosal immune response, yet the and their receptors in the recruit- mechanism by which this process occurs remains to be fully defined. Here we ment of activated lymphocyte sub- show that the CC chemokine receptor 9 (CCR9) is selectively and functionally sets to effector tissues (5). For exam- + + expressed on murine αEβ7 naive CD8αβ lymphocytes and a subset of recent- ple, the CC chemokine receptor 4 ly activated CD69+ CD8αβ+ lymphocytes. Using a T cell receptor transgenic (CCR4) and the CCR10 ligand, transfer model, we demonstrate that CCR9 expression is functionally main- CCL27, were recently shown to con- tained on CD8αβ+ lymphocytes following activation in mesenteric lymph tribute to lymphocyte recruitment to nodes but rapidly downregulated on CD8αβ+ lymphocytes activated in periph- inflamed skin (6, 7). The chemokine eral lymph nodes. These recently activated CCR9+ CD8αβ+ lymphocytes selec- receptor CCR9 is selectively and tively localized to the small-intestinal mucosa, and in vivo neutralization of the functionally expressed on human CCR9 ligand, CCL25, reduced the ability of these cells to populate the small- small-intestinal lymphocytes (8), and intestinal epithelium. Together these results demonstrate an important role its ligand, CCL25, is constitutively for chemokines in the localization of T lymphocytes to the small-intestinal expressed by murine and human mucosa and suggest that targeting CCL25 and/or CCR9 may provide a means small-intestinal epithelial cells (9, to selectively modulate small-intestinal immune responses. 10), indicating a potential role for This article was published online in advance of the print edition. this chemokine receptor/chemokine The date of publication is available from the JCI website, http://www.jci.org. pair in lymphocyte localization to the J. Clin. Invest. 110:1113–1121 (2002). doi:10.1172/JCI200215988. small intestine. However, examina- tion of CD8αβ+ lymphocyte numbers in the small-intestinal epithelium of Introduction recruitment of T lymphocytes to intes- CCR9–/– mice has yielded conflicting The intestinal mucosa is continually tinal effector sites is thought to play a results (11, 12). Furthermore, small- exposed to a large array of foreign anti- critical role in this process. intestinal epithelial cells constitu- gens and must respond appropriately to Following activation in secondary tively express a number of maintain mucosal integrity while at the lymphoid organs, T lymphocytes gain chemokines with activity for T lym- same time mounting effective immune the ability to migrate from the blood phocytes, including CXCL12, CCL28, responses to potential pathogens. The to tertiary effector tissues such as the and CX3CL1, indicating a potential intestine and skin (1). Subsets of pre- role for other chemokines in this Received for publication May 23, 2002, and viously activated T lymphocytes dis- process (13–15). Thus the in vivo role accepted in revised form August 20, 2002. play selective tissue tropism for these of CCL25 and CCR9 in T lymphocyte Address correspondence to: William W. sites, a process that is controlled by recruitment to the small intestine Agace, Immunology Section, Department of specific combinations of cell adhesion remains unclear. Cell and Molecular Biology, Lund University, molecules (1, 2). Previously activated In the current study we have exam- BMC I-13, S-22184 Lund, Sweden. T lymphocytes homing to the intes- ined expression and regulation of Phone: 46-46-2220416; Fax: 46-46-2224218; + E-mail: [email protected]. tine express high levels of α4β7 inte- CCR9 on murine CD8αβ lympho- Conflict of interest: No conflict of interest grin, whose ligand, MAdCAM-1, is cytes in vivo and determined the role has been declared. expressed on postcapillary venules in of CCL25 in the recruitment of recent- Nonstandard abbreviations used: CC the intestinal lamina propria. Indeed, ly activated CD8αβ+ lymphocytes to chemokine receptor (CCR); ovalbumin (OVA); 5- and 6-carboxy-fluorescein diacetate β7 integrin appears to be critical for the small-intestinal mucosa. succinimidyl ester (CFSE); intraepithelial the entry of previously activated T lymphocyte (IEL); lamina propria lymphocyte lymphocytes into the intestinal lami- Methods (LPL); lymph node (LN); mesenteric lymph na propria and epithelium (3, 4). Mice. C57BL/6J-Ly5.1 mice were node (MLN); peripheral lymph node (PLN); T cell receptor (TCR); gut-associated In addition to cell adhesion mole- obtained from Charles River Labora- lymphoid tissue (GALT). cules, accumulating evidence exists tories (Wilmington, Massachusetts, The Journal of Clinical Investigation | October 2002 | Volume 110 | Number 8 1113 USA). OT-1 mice were kindly provided 5- and 6-carboxy-fluorescein diac- incubated with fluorochrome-conju- by A. Mowat (Glasgow, United King- etate succinimidyl ester (CFSE) stain- gated or biotin-conjugated antibody dom). All mice were maintained at the ing, cells (107 cells/ml) were incu- at saturating concentrations for 20 animal facility at the Department of bated with 1 µM CFSE (Molecu- minutes at 4°C. For biotinylated Microbiology, Immunology and Gly- lar Probes Inc., Eugene, Oregon, antibodies, stained cells were washed cobiology, Lund University, and were USA) for 8 minutes at room temp- and fluorochrome-conjugated strep- used between 8 and 14 weeks of age. erature in PBS. tavidin was added to the cells for 20 Antibodies and reagents. Anti-CD8β Lymphocyte isolation. Small-intestin- minutes at 4°C. For CCR9 staining, (53-5.8), anti-Ly5.2 (104), anti- al and colonic intraepithelial lym- 10% normal goat serum was included CD62L (Mel-14), anti-CD44 (IM7), phocytes (IELs) were isolated as pre- in the initial blocking buffer. Cells anti-CD4 (RM4-5), and anti-CD69 viously described (17) or from the cell were then incubated with polyclonal (H1.2F3) antibodies and strepta- suspensions obtained following rabbit anti–mouse CCR9 antibody vidin-allophycocyanin were from EDTA treatment of intestinal tissue for 45 minutes at 4°C, washed, and Pharmingen (San Diego, California, (see below). Small-intestinal lamina incubated with biotinylated goat USA). Anti-αE (M290) and anti-β7 propria lymphocytes (LPLs) were iso- anti-rabbit antibody for 20 minutes (FIB-504) antibodies were kindly pro- lated essentially as previously at 4°C. Finally, cells were incubated vided by C. Parker (Dana-Farber Can- described (18). Briefly, intestinal with fluorochrome-conjugated strep- cer Institute, Boston, Massachusetts, pieces were incubated for 4 × 20 to tavidin for 20 minutes at 4°C. To USA). Hybridomas producing anti- 6 × 20 minutes in calcium- and mag- check staining specificity, anti-CCR9 CD8α (YTS 169-4), anti-CD4 nesium-free (CMF) HBSS supple- antibody was preincubated with the (GK1.5), anti-B220 (RA3.6B2), anti– mented with 10% FCS and 10 mM immunizing peptide used for genera- FcRII/III (2.4G2), and anti–MHC-II HEPES (GIBCO BRL; Life Technolo- tion of the CCR9 antibody (PTELT- (M5/114) antibodies were from gies, Paisley, Scotland, United King- SLIPGMFDDFSYDST; 5 µg/ml) for American Type Culture Collection dom) (HBSS-10), containing 5 mM 15 minutes at room temperature (Rockville, Maryland, USA).
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