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CCL21 Transgenic Expression of the CC Chemokine of the Thyroid Gland Generated by a Novel Model for Lymphocytic Infiltration

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CCL21 Transgenic Expression of the CC Chemokine of the Thyroid Gland Generated by a Novel Model for Lymphocytic Infiltration A Novel Model for Lymphocytic Infiltration of the Thyroid Gland Generated by Transgenic Expression of the CC Chemokine CCL21 This information is current as of September 25, 2021. Andrea P. Martin, Elizabeth C. Coronel, Gen-ichiro Sano, Shu-Cheng Chen, Galya Vassileva, Claudia Canasto-Chibuque, Jonathon D. Sedgwick, Paul S. Frenette, Martin Lipp, Glaucia C. Furtado and Sergio A. Lira J Immunol 2004; 173:4791-4798; ; Downloaded from doi: 10.4049/jimmunol.173.8.4791 http://www.jimmunol.org/content/173/8/4791 http://www.jimmunol.org/ References This article cites 61 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/173/8/4791.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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Novel Model for Lymphocytic Infiltration of the Thyroid Gland Generated by Transgenic Expression of the CC Chemokine CCL211 Andrea P. Martin,2* Elizabeth C. Coronel,2† Gen-ichiro Sano,* Shu-Cheng Chen,† Galya Vassileva,† Claudia Canasto-Chibuque,* Jonathon D. Sedgwick,‡ Paul S. Frenette,* Martin Lipp,§ Glaucia C. Furtado,2* and Sergio A. Lira3* Lymphocytic infiltrates and lymphoid follicles with germinal centers are often detected in autoimmune thyroid disease (AITD), but the mechanisms underlying lymphocyte entry and organization in the thyroid remain unknown. We tested the hypothesis that CCL21, a chemokine that regulates homeostatic lymphocyte trafficking, and whose expression has been detected in AITD, is involved in the migration of lymphocytes to the thyroid. We show that transgenic mice expressing CCL21 from the thyroglobulin Downloaded from promoter (TGCCL21 mice) have significant lymphocytic infiltrates, which are topologically segregated into B and T cell areas. Although high endothelial venules expressing peripheral lymph node addressin were frequently observed in the thyroid tissue, lymphocyte recruitment was independent of L-selectin or lymphotoxin-␣ but required CCR7 expression. Taken together, these results indicate that CCL21 is sufficient to drive lymphocyte recruitment to the thyroid, suggest that CCL21 is involved in AITD pathogenesis, and establish TGCCL21 transgenic mice as a novel model to study the formation and function of lymphoid follicles http://www.jimmunol.org/ in the thyroid. The Journal of Immunology, 2004, 173: 4791–4798. he autoimmune thyroid diseases (AITD)4 are the most autoantibodies directed against thyroid Ags such as thyroglobulin common autoimmune endocrine diseases, affecting (TG), thyroid peroxidase, and the thyroid-stimulating hormone T ϳ1.5% of the general population (1). The major forms of (TSH) receptor (TSH-R) (2). These autoantibodies can either stim- AITD are Hashimoto’s thyroiditis (HT), causing hypothyroidism, ulate or inhibit thyroid function. and Graves’ disease (GD), causing hyperthyroidism. The hallmark Despite substantial clinical and experimental data supporting a of these conditions is thyroid dysfunction associated with the pres- role for lymphocytes in triggering and sustaining AITD, factors ence of lymphocytic infiltrates in the thyroid (2, 3). In HT, there is responsible for their recruitment and retention in the thyroid remain by guest on September 25, 2021 a diffuse lymphocytic infiltration with the presence of macro- uncertain. Migration of T cells appears to be regulated by inflamma- phages and destroyed thyrocytes. The lymphocytes often cluster to tory (inducible) and constitutive chemokines. Examples of inflamma- form lymphoid follicles with germinal centers. Lymphocytic infil- tory chemokines include CXCL8, CCL2, CCL3, CCL4, and trates, usually without germinal center formation, are also seen in CXCL10. Expression of these chemokines occurs during inflam- GD (4), but diffuse follicular cell hyperplasia and increased vas- mation and is required for attraction of specific leukocyte subsets cularity, rather than thyrocyte destruction, are observed (3). mediating inflammatory reactions (6, 7). CXCL10, the best studied The etiopathogenic role of lymphocytes in HT and GD has been of the inflammatory chemokines regulating T cell migration, is in- amply studied and a variety of effector mechanisms have been ␥ defined for both T and B cells (2, 5). T cells cause thyroid de- duced by IFN- , a key cytokine involved in inflammation and im- struction directly, via cytotoxicity, or indirectly, through cytokines mune regulation (8). CXCL10 interacts with CXCR3, a chemokine that induce apoptosis of thyroid follicle cells (5). B cells produce receptor expressed by effector T cells and endothelial cells (9). Chemokines constitutively produced by lymphoid organs (CCL19, CCL21, CXCL12, and CXCL13) are involved in physi- *Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029; ological trafficking of leukocytes and their segregation into spe- †Schering-Plough Research Institute, Kenilworth, NJ 07033; ‡DNAX Research, Palo cialized compartments. Among these, CCL19 and CCL21 are the Alto, CA 94304; and §Max-Delbruck-Center for Molecular Medicine, Berlin, Germany best-characterized chemokines regulating homeostatic T cell mi- Received for publication June 4, 2004. Accepted for publication July 30, 2004. gration. Both chemokines interact with a common receptor, CCR7, 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 which is expressed by naive and memory T cells (10). CCL21 and with 18 U.S.C. Section 1734 solely to indicate this fact. CCL19 are displayed by high endothelial venules (HEVs) and ac- 1 S.A.L. is an Irene Diamond Associate Professor of Immunology. This work was tivate integrins after interaction with CCR7 present on circulating supported in part by a grant from the Irene Diamond Fund, and by Grants DK 067989 lymphocytes (11). The functional consequence of integrin activa- (to S.A.L.) and HL 69438 (to P.S.F.) from the National Institutes of Health. tion is increased adhesiveness of lymphocytes to the endothelium, 2 A.P.M., E.C.C., and G.C.F. contributed equally to the manuscript. a key step in lymphocyte transendothelial migration. Accordingly, 3 Address correspondence and reprint requests to Dr. Sergio A. Lira, Immunobiology Center, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1630, New mice lacking CCR7, CCL19, and CCL21 have defective homing of York, NY, 10029-6574. E-mail address: [email protected] T cells into lymphoid tissue (12–14). In addition to controlling the 4 Abbreviations used in this paper: AITD, autoimmune thyroid diseases; HT, Hashi- initial aspects of lymphocyte migration, chemokines also control moto’s thyroiditis; GD, Graves’ disease; TG, thyroglobulin; TSH, thyroid-stimulating hormone; HEV, high endothelial venule; Lt␣, lymphotoxin ␣; PNAd, peripheral targeted homing of T and B cells within lymphoid organs. The lymph node addressin; LDL, low density lipoprotein. specific segregation of B and T cells in secondary lymphoid organs Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 4792 TRANSGENIC EXPRESSION OF CCL21 IN THE THYROID is dependent on multiple chemokine gradients established by den- River Laboratories, Wilmington, MA) according to published procedures dritic cells, stromal cells, and lymphocytes (15). (33). Genotyping of the TGCCL21 transgenic founders and progeny was Chemokines, with the exception of CXCL12 (16), are not ex- conducted by PCR analysis of mouse tail DNA using recognition primers for the rat TG promoter 5Ј-CTG CAG ACA AGC AGG CAT GCA-3Ј pressed by the normal human thyroid at appreciable levels. How- (forward) and 5Ј-CAC ACA TGG CAC ATA TGC-3Ј (reverse) as previ- ever, most chemokines studied to date are expressed within the ously described (34). The endogenous low density lipoprotein gene (LDL) thyroids of GD and HT patients. These include CXC chemokines, was used as an internal control using primers LDLL 5Ј-CGC AGT GCT CXCL1 (17), the IFN-␥ inducible chemokines CXCL9, and CCT CAT CTG ACT TGT-3Ј (forward) and LDLU 5Ј-ACC CCA AGA CGT GCT CCC AGG ATG A-3Ј (reverse). PCR conditions were 94°C, CXCL10 (9, 18, 19), CXCL12 (16), and CXCL13 (20). The CC 30 s; 60°C, 30 s; 72°C, 60 s for 30 cycles. chemokines CCL2, CCL3, CCL4, and CCL5 are also reported to TGCCL21 transgenic mice (line 24) were crossed to CCR7Ϫ/Ϫ mice, be expressed in thyroid disease (19, 21, 22). Thyroid expression of described by Forster et al. (12), to LT␣Ϫ/Ϫ (35) and to RAG-2Ϫ/Ϫ mice these chemokines may be critical for the recruitment of chemokine (36). Mice hemizygous for CCL21 and null for RAG or CCR7 or LT␣ (referred to as TGCCL21/RAGϪ/Ϫ mice, TGCCL21/CCR7Ϫ/Ϫ mice, and receptor-expressing leukocytes to the thyroid. Indeed, CXCR3,
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