Adult Thymic Epithelium Contains Nonsenescent Label-Retaining Cells

Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire+ cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire+ cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire’s unique property of generating a self-tolerant T cell repertoire is functional only in mTECs.

Section: Epcamsupporting

confidence: 82%

Ectopic Aire Expression in the Thymic Cortex Reveals Inherent Properties of Aire as a Tolerogenic Factor within the Medulla

Nishijima

Kitano

Miyachi

et al. 2015

“…Although the functional importance of this effect has yet to be demonstrated, we propose that it may contribute to the dramatic changes in TEC subsets that occur in the neonatal period: expansion of the mTEC compartment in the first weeks of life is accompanied by an abrupt decrease in the number of cTEC (19). Therefore, although cTEC are the dominant TEC subset at birth, they represent only 10% of TEC in adults (60). Moreover, we confirmed that the impact of AIRE-dependent pGE is not limited to generation of TRA.…”

Section: Discussionmentioning

confidence: 91%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

Self Cite

Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non–cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell–cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.

“…We next addressed whether the reduction in TEC numbers might reflect a specific decline in the mTEC or cTEC compartment. The abundance of cTECs peaks around birth, whereas the frequency of cTECs in young adult mice is low (34). Therefore, we also analyzed the mTEC/cTEC ratio in newborn mice (P3) and found that it was not affected in FoxN1-Gpr177 mice (Supplemental Fig.…”

Section: Foxn1-gpr177 Tecs Have a Higher Apoptosis Rate But Proliferamentioning

confidence: 99%

Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development

Brunk

Augustin

Meister

et al. 2015

Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery.