CCR7-mediated Migration of Developing Thymocytes to the Medulla is Essential for Negative Selection to Tissue-restricted Antigens

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Oct 7

PMID 19805112

Citations 69

Authors

Takeshi Nitta

Sachiko Nitta

Yu Lei

Martin Lipp

Yousuke Takahama

Affiliations

Soon will be listed here.

Abstract

Immature double-positive thymocytes are generated in the thymic cortex, and on positive selection, are induced to differentiate into mature single-positive thymocytes and relocate to the medulla. CCR7 is pivotal for cortex-to-medulla migration of positively selected thymocytes, and CCR7-mediated migration to the medulla is essential for establishing central tolerance, thereby, preventing tissue-specific autoimmunity. However, it was unclear how CCR7-mediated migration to the medulla affects the establishment of self-tolerance. Here, we show that the deletion of thymocytes specific for insulin-promoter-driven tissue-restricted antigens (TRAs) is significantly impaired in CCR7- or CCR7-ligand-deficient mice. These results indicate that CCR7-mediated migration to the medulla contributes to the negative selection of TRA-reactive thymocytes.

Citing Articles

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References

Gallegos A, Bevan M . Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med. 2004; 200(8):1039-49. PMC: 2211843. DOI: 10.1084/jem.20041457. View

Kaye J, HSU M, Sauron M, Jameson S, Gascoigne N, Hedrick S . Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 1989; 341(6244):746-9. DOI: 10.1038/341746a0. View

Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E . CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999; 99(1):23-33. DOI: 10.1016/s0092-8674(00)80059-8. View

Hogquist K, Jameson S, Heath W, Howard J, Bevan M, Carbone F . T cell receptor antagonist peptides induce positive selection. Cell. 1994; 76(1):17-27. DOI: 10.1016/0092-8674(94)90169-4. View

Ueno T, Saito F, Gray D, Kuse S, Hieshima K, Nakano H . CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med. 2004; 200(4):493-505. PMC: 2211934. DOI: 10.1084/jem.20040643. View

Gommeaux J, Gregoire C, Nguessan P, Richelme M, Malissen M, Guerder S . Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol. 2009; 39(4):956-64. DOI: 10.1002/eji.200839175. View

Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y . The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008; 29(3):423-37. DOI: 10.1016/j.immuni.2008.06.015. View

Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N . CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity. 2006; 24(2):165-77. DOI: 10.1016/j.immuni.2005.12.011. View

Bonasio R, Scimone M, Schaerli P, Grabie N, Lichtman A, von Andrian U . Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol. 2006; 7(10):1092-100. DOI: 10.1038/ni1385. View

10.

Takahama Y . Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol. 2006; 6(2):127-35. DOI: 10.1038/nri1781. View

11.

Hopken U, Wengner A, Loddenkemper C, Stein H, Heimesaat M, Rehm A . CCR7 deficiency causes ectopic lymphoid neogenesis and disturbed mucosal tissue integrity. Blood. 2006; 109(3):886-95. DOI: 10.1182/blood-2006-03-013532. View

12.

Anderson M, Venanzi E, Chen Z, Berzins S, Benoist C, Mathis D . The cellular mechanism of Aire control of T cell tolerance. Immunity. 2005; 23(2):227-39. DOI: 10.1016/j.immuni.2005.07.005. View

13.

Davalos-Misslitz A, Rieckenberg J, Willenzon S, Worbs T, Kremmer E, Bernhardt G . Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur J Immunol. 2007; 37(3):613-22. DOI: 10.1002/eji.200636656. View

14.

Davalos-Misslitz A, Worbs T, Willenzon S, Bernhardt G, Forster R . Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice. Blood. 2007; 110(13):4351-9. DOI: 10.1182/blood-2007-01-070284. View

15.

Honey K, Nakagawa T, Peters C, Rudensky A . Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J Exp Med. 2002; 195(10):1349-58. PMC: 2193748. DOI: 10.1084/jem.20011904. View

16.

Liston A, Gray D, Lesage S, Fletcher A, Wilson J, Webster K . Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med. 2004; 200(8):1015-26. PMC: 2211852. DOI: 10.1084/jem.20040581. View

17.

Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y . The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity. 2008; 29(3):438-50. DOI: 10.1016/j.immuni.2008.06.018. View

18.

Kwan J, Killeen N . CCR7 directs the migration of thymocytes into the thymic medulla. J Immunol. 2004; 172(7):3999-4007. DOI: 10.4049/jimmunol.172.7.3999. View

19.

Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y . Regulation of CD8+ T cell development by thymus-specific proteasomes. Science. 2007; 316(5829):1349-53. DOI: 10.1126/science.1141915. View

20.

Zhu M, Chin R, Tumanov A, Liu X, Fu Y . Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J Immunol. 2007; 179(12):8069-75. DOI: 10.4049/jimmunol.179.12.8069. View