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231115072.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Dartmouth Digital Commons (Dartmouth College) Dartmouth College Dartmouth Digital Commons Open Dartmouth: Faculty Open Access Articles 8-2003 CCR5 Mediates Specific iM gration of Toxoplasma Gondii—Primed CD8+ Lymphocytes to Inflammatory Intestinal Epithelial Cells Souphalone Luangsay Dartmouth College Lloyd H. Kasper Dartmouth College Nicolas Rachinel Dartmouth College Laurie A. Minns Dartmouth College Follow this and additional works at: https://digitalcommons.dartmouth.edu/facoa Part of the Digestive System Diseases Commons, and the Gastroenterology Commons Recommended Citation Luangsay, Souphalone; Kasper, Lloyd H.; Rachinel, Nicolas; and Minns, Laurie A., "CCR5 Mediates Specific iM gration of Toxoplasma Gondii—Primed CD8+ Lymphocytes to Inflammatory Intestinal Epithelial Cells" (2003). Open Dartmouth: Faculty Open Access Articles. 593. https://digitalcommons.dartmouth.edu/facoa/593 This Article is brought to you for free and open access by Dartmouth Digital Commons. It has been accepted for inclusion in Open Dartmouth: Faculty Open Access Articles by an authorized administrator of Dartmouth Digital Commons. For more information, please contact [email protected]. GASTROENTEROLOGY 2003;125:491–500 CCR5 Mediates Specific Migration of Toxoplasma gondii–Primed CD8؉ Lymphocytes to Inflammatory Intestinal Epithelial Cells SOUPHALONE LUANGSAY,* LLOYD H. KASPER,* NICOLAS RACHINEL,* LAURIE A. MINNS,* FRANCK J. D. MENNECHET,* ALAIN VANDEWALLE,‡ and DOMINIQUE BUZONI–GATEL§ *Departments of Microbiology and Immunology and Medicine, Dartmouth Medical School, Lebanon, New Hampshire; ‡INSERM Unite´ 478, Faculte´deMe´decine Xavier Bichat, Paris, France; and §De´partement de Parasitologie, Institut Pasteur, and De´partement de Sante´ Animale, Institut National de la Recherche Agronomique, Paris, France Background & Aims: Toxoplasma gondii, an obligate in- creted at the surface of intestinal epithelial cells (IECs) tracellular parasite, can invade intestinal epithelial cells play a critical role in the initiation and modulation of the and elicit a robust Th1 immune response. In this model immune response to various pathogens.1 In humans, ؉ of intestinal inflammation, CD8 intraepithelial lym- IECs from inflamed intestines secrete inflammatory cy- phocytes (IELs) secrete transforming growth factor tokines; in mice, intestinal lesions due to invasive patho- (TGF)-␤, which appears necessary for the maintenance gens are more frequently characterized by acute neutro- of homeostasis in the intestine. However, the mecha- nism responsible for the IEL migration to the inflamed phil infiltrations associated with increased levels of intestine is still unclear. Methods: An in vitro coculture macrophage inflammatory protein (MIP)-2 produced by cell system was used to quantify the IEL attraction by an infected IECs.2,3 Other chemokines may act as chemoat- infected intestinal epithelial cell line (m-ICcl2). We used tractants for macrophages/monocytes/neutrophils and/or CCR5-deficient mice to determine which chemokine re- lymphocytes.4 ceptor–chemokine interaction could be responsible for Intestinal intraepithelial lymphocytes (IELs), mainly the recruitment of antigen-specific CD8؉ IELs to the composed of CD8␣ϩ subsets of lymphocytes (CD8␣␣ϩ small intestine for the promotion of parasite clearance and CD8␣␤ϩ IELs), are present in the gastrointestinal and host recovery. Results: We observed increased ex- tract and express chemokine receptors, including CCR2, pression of several chemokine receptors (CCR1, CCR2, CXCR3, CCR5, and CCR9. Some of these receptors are CCR5, CXCR3) in the infected ileum. In particular, CCR5 up-regulated during intestinal inflammation and are per- expression was markedly increased in antigen-primed haps critical in lymphocyte localization within intestinal CD8؉ IELs. Experiments using recombinant chemokines mucosa. Recently, a specialized interaction has been de- as well as blocking antibodies showed that macrophage ϩ ϩ inflammatory protein (MIP)-1␣ and MIP-1␤ were critical scribed between both CD8 IELs and CD4 T cells from for their homing. CD8؉ IELs isolated from CCR5-defi- the lamina propria expressing CCR9 and IECs through cient mice (CCR5؊/؊), despite their high production of the interaction with its ligand, the thymus-expressed TGF-␤ and overexpression of activation markers, were chemokine (CCL25), which appears to be highly ex- 5,6 impaired in their ability to migrate in vitro to the m-ICcl2 pressed in crypt intestinal cells. Such specific chemo- monolayer or in vivo to the inflamed intestine after kine-lymphocyte receptor interaction in the normal gas- adoptive transfer. Conclusions: Our data emphasize the trointestinal tract suggests that the expression of biologic role of CCR5 as an important component in the chemokines by differentiated epithelium represents an -migration of intraepithelial CD8؉ T cells and the regula tion of the inflammatory response following parasite infection. Abbreviations used in this paper: CFSE, 5(6) carboxyfluorescein diacetate, succinimidyl ester; IEC, intestinal epithelial cell; IEL, intra- epithelial lymphocyte; IL, interleukin; IP-10, interferon ␥–inducible 10-kilodalton protein; MIP, macrophage inflammatory protein; MCP, principal biologic function of the intestinal muco- monocyte chemoattractant protein; RANTES, regulated upon activa- Asal surface is to maintain immunologic homeostasis tion, normal T cell expressed and secreted protein; TGF, transforming in response to foreign antigens. The enterocytes lining growth factor; WT, wild-type. © 2003 by the American Gastroenterological Association the villus wall of the intestine form a tight barrier 0016-5085/03/$30.00 against potentially invasive pathogens. Chemokines se- doi:10.1016/S0016-5085(03)00903-X 492 LUANGSAY ET AL. GASTROENTEROLOGY Vol. 125, No. 2 important mechanism for specialized immune responses. CD8␤ϩ IELs were purified by incubation with either anti- This interaction may allow for homeostatic balance in the CD8␣ microbeads (Miltenyi Biotec, Auburn, CA) or anti- normal gut.6,7 CD8␤ antibody (BD Pharmingen, San Diego, CA) followed by Toxoplasma gondii, an obligate intracellular parasite anti-rat immunoglobulin G microbeads (Miltenyi Biotec) and acquired by oral infection and responsible for acute and separated with a magnetically activated cell sorting column ϩ ϩ lethal ileitis in susceptible C57BL/6 mice, can invade (Miltenyi Biotec). CD8␣ and CD8␤ staining (BD Pharm- IECs, eliciting a robust immune response that is associ- ingen) confirmed 98% pure populations. Surface expression ␣ ated with increased production of chemokines.8,9 In T. was assessed with CCR5, E (CD103), CD25, Ly-6C, and gondii–infected and –inflamed intestines, the composi- Ox40 (CD134) (BD Pharmingen). tion of infiltrating cells is predominantly represented by Culture of m-IC Cells and Infection CD8ϩ IELs and CD4ϩ lymphocytes, which confer the cl2 by T. gondii main components of protective immunity to T. gon- ϩ b 14 dii.9–11 The CD8 IELs have been shown to promote IECs from the m-ICcl2 cell line (C57BL/6, H-2 ) were host recovery and parasite clearance. When adoptively seeded upside down on collagen I–coated Transwell filters transferred, infiltrating CD8␣␤ TCR␣␤ IELs provide (5 ϫ 105 cells/filter; ID, 6.5 mm; pore size, 3 ␮m; Costar long-term immunity and protect mice against a lethal Transwell, Fisher Scientific, Pittsburgh, PA) and cultured for parasite challenge in a transforming growth factor 10 days in a modified defined medium as previously de- 8,9 (TGF)-␤–dependent manner.8,10 The preferential re- scribed. The integrity of the infected monolayer was con- cruitment of these cells to infected intestinal sites ap- firmed microscopically before each experiment and infected pears to be critical for the control of the inflammatory with 2:1 parasites cells. For the in vitro infection, tachyzoits from the RH strain of T. gondii were used. All experiments cellular response.12 Although the ␣4␤7 and ␣E␤7 inte- were performed on 3 separate filters for each condition tested grins expressed at the cell surface of lymphocytes may and then repeated in at least 3 different experiments. partially explain IEL trafficking,12 other molecules in- cluding IEC-expressed chemokines may act as chemoat- In Vitro Migration Assay tractants.8,9 ␣ϩ In this study, we show that the secretion of beta Unprimed and primed CD8 IELs incubated with a ␮ chemokines MIP-1␣ (CCL3) and MIP-1␤ (CCL4) by cell dye 5-chloromethylflurorescein diacetate (10 mol/L) enterocytes can orchestrate the recruitment of CD8ϩ (Molecular Probes, Eugene, OR) were added to the upper IELs via CCR5 to enhance the immune response against chamber of confluent m-ICcl2 cells grown on Transwell as previously described (5 ϫ 105 IELs/filter; Costar Transwell) T. gondii infection. These results show the immunologic without or with blocking antibodies to MIP-1␣ and MIP-1␤ potential of IECs expressing specific chemokines for the (1 and 10 ␮g/mL) or with their irrelevant control anti-goat trafficking and control of intestinal IELs in this patho- immunoglobulin G (R&D Systems, Minneapolis, MN). m- gen-driven model of intestinal inflammatory disease. ICcl2 cells and IELs were incubated for 4 hours at 37°C. To visualize the IELs in the monolayer, filters were stained with Materials and Methods propidium iodide and rhodamine-phalloidin (Molecular Mice and T. gondii Infection Probes) and observed by confocal laser scanning microscopy (MRC 1024; Bio-Rad,
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