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

Abstract

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 cortico-medullary 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 CD80high medullary epithelial cells (mTECs), 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 upregulation of selected CCR4 and CCR7 ligands, which induced selective migration of double-positive (DP) and single positive (SP) 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 mTECs and alters the coordinated maturation and migration of thymocytes. These results suggest a novel mechanism behind the Aire-dependent induction of central tolerance.

Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

“…Previous studies indicated that Aire not only facilitated the ectopic expression of tissue-restricted self-Ags, but also promoted the expression of several chemokines, including CCL21, a CCR7L chemokine, and XCL1 in mTECs (6,7). It was also shown that the expression of CCL21 in mTECs was enhanced by signals through the lymphotoxin b receptor (LTbR) (8,9), of which its ligand, lymphotoxin, was provided by positively selected thymocytes (10,11).…”

“…It was previously shown that CCL21 mRNA expression was reduced in mTECs from Aire-deficient mice (6,7). To examine whether Aire affects the cellularity of CCL21-expressing mTECs, we examined mTEC subpopulations in Aire-deficient mice.…”

A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

“…3A). Second, we and other groups [38,39] have reported that Aire deficiency results in altered expression of thymic chemokines. Specifically, the ligands for chemokine receptors Ccr4 and Ccr7, which coordinate the intrathymic migration of thymocytes, as well as for Xcl1, which mediates the medullary accumulation of DCs, are downregulated in the Aire-KO thymus.…”

“…Accordingly, the NF-κB-responsive CNS1 enhancer region is the link connecting the well-known effect of RANK signaling to the expression of Aire in mTECs. In this way, RANK signaling has a dual effect on mTEC function: (i) As an inducer of mTEC maturation and (ii) activator of Aire expression.In addition to its well-described effect on TSA induction, Aire has been shown to modulate the expression of thymic chemokines that are required for migration of developing thymocytes and thymic DCs [38,39]. Additionally, as the expression of mTEC differentiation markers is skewed in the Aire-KO mouse, Aire has been suggested to promote the maturation program of mTECs [14,40,41].…”

Induction de la tolérance centrale dans le thymus par le facteur de transcription Aire

“…Aire régule l'expression de CCL (CC-type chemokine) 17/CCL22 et CCL19/CCL21, ligands respectifs des récepteurs des chimiokines CCR (C-C chemokine receptor type) 4 et CCR7, qui sont nécessaires à la migration des thymocytes dans la médulla (Figure 3) [41,42]. La déficience en CCR7 entraîne un défaut de migration des cellules T au sein de la médulla, et donc un défaut dans l'induction de la tolérance centrale [43].…”