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Autoimmune Regulator Deficiency Results in Decreased Expression of CCR4 and CCR7 Ligands and in Delayed Migration of CD4⁺ Thymocytes¹

Martti Laan,^2* Kai Kisand,^* Vivian Kont,^* Kaidi Möll,^* Liina Tserel,^* Hamish S. Scott, and Pärt Peterson^*

*Molecular Pathology Group and Immunology Group, Institute of General and Molecular Pathology, Tartu University, Tartu, Estonia; Division of Molecular Pathology, Institute of Medical and Veterinary Science and Centre for Cancer Biology, Hanson Institute, Adelaide, Australia; and The School of Medicine, University of Adelaide, Australia

Autoimmune regulator (Aire) has been viewed as a central player in the induction of tolerance. This study examines whether Aire can modulate the production of the thymic chemokines involved in corticomedullary migration and thus play a role in intrathymic thymocyte migration and maturation. Aire deficiency resulted in reduced gene expression and protein levels of the CCR4 and CCR7 ligands in whole thymi of mice, as determined by quantitative PCR analysis and ELISA. The expression of the CCR4 ligands coincided with Aire expression in the CD80^high medullary thymic epithelial cells, whereas the expression of the CCR7 ligands was detected in other cell populations. Also, the expression pattern of the CCR4 and CCR7 ligands follows that of Aire during postnatal but not during embryonic development. In vitro, overexpression of Aire resulted in an up-regulation of selected CCR4 and CCR7 ligands, which induced selective migration of double-positive and single-positive CD4⁺ cells. In vivo, Aire deficiency resulted in a diminished emigration of mature CD4⁺ T cells from the thymi of 5-day-old mice. In conclusion, Aire regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes. These results suggest a novel mechanism behind the Aire-dependent induction of central tolerance.

² Address correspondence and reprint requests to Dr. Martti Laan, Molecular Pathology, Biomedicum, Ravila 19, Tartu 50414, Estonia. E-mail address: martti.laan{at}ut.ee

¹ This work was supported by Eurothymaide and EURAPS, 6th Frame Program of the European Union (to P.P. and H.S.S.), by a Wellcome Trust senior fellowship grant (to P.P.), by National Health and Medical Research Council Fellowships 171601 and 461204, by National Health and Medical Research Council Program Grants 257501, 264573, and 406700 (to H.S.S.), by Estonian Science Foundation Grants 7559, 7197, and 6663 (to M.L., K.K., and P.P.), by the European Regional Fund and Archimedes Foundation (to M.L., K.K., and P.P.), and by Estonian Targeted Financiation Grant SF0180021s07 (to P.P.).