Aire Disruption Influences the Medullary Thymic Epithelial Cell Transcriptome and Interaction With Thymocytes

Abstract

The function of medullary thymic epithelial cells (mTECs) is associated with thymocyte adhesion, which is crucial for the negative selection of autoreactive thymocytes in the thymus. This process represents the root of central tolerance of self-components and prevents the onset of autoimmune diseases. Since thymic epithelia correspond to an important target of donor T cells during the onset of chronic graft-vs-host-disease, mTEC-thymocyte adhesion may have implications for alloimmunity. The Aire and Fezf2 genes function as transcriptome controllers in mTECs. The central question of this study is whether there is a mutual relationship between mTEC-thymocyte adhesion and the control of the mTEC transcriptome and whether Aire is involved in this process. Here, we show that in vitro mTEC-thymocyte adhesion causes transcriptome changes in mTECs and upregulates the transcriptional expression of Aire and Fezf2, as well as cell adhesion-related genes such as Cd80 or Tcf7, among others. Crispr-Cas9-mediated Aire gene disruption demonstrated that this gene plays a role in the process of mTEC-thymocyte adhesion. Consistent with the nuclear localization signal (NLS) encoded by Aire exon 3, which was targeted, we demonstrate that Aire KO−/− mTECs impair AIRE protein localization in the nucleus. Consequently, the loss of function of Aire reduced the ability of these cells to adhere to thymocytes. Their transcriptomes differed from their wild-type Aire+/+ counterparts, even during thymocyte adhesion. A set of mRNA isoforms that encode proteins involved in cell adhesion were also modulated during this process. This demonstrates that both thymocyte interactions and Aire influence transcriptome profiling of mTEC cells.

Resveratrol ameliorates thymus senescence changes in D‐galactose induced mice

“…31 Aire is also a vital transcriptional regulator in mTECs which plays significant roles in the process of controlling mTECthymocyte adhesion. 32 Consistent with this, our data suggested that CD4+ T cells decreased and CD8+ T cells increased in mice with reduced Aire expression. We demonstrated that RSV supplementation improved the Aire mRNA relative expression greatly.…”

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

“…This suggests that the expansion of SP thymocytes occurring between D12 and D28 might have led to the increase in mTEC numbers. This is consistent with the fact that the development of the mTEC compartment during embryogenesis requires interaction between TECs and positively selected thymocytes (25)(26)(27)(28)(29)(30)(31), and suggests that a similar crosstalk is instrumental to the maintenance of mTECs in the adult thymus. Representative profiles of cTECs and mTECs at different time points during pregnancy and postpartum regeneration are shown in Supplementary Figure 1.…”

Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

“…At this stage, medullary thymic epithelial cells orchestrate the presentation of antigens from virtually all organs to maturing thymocytes via MHC type II molecules expressed on thymic dendritic cells (19) . This process called promiscuous gene expression is highly regulated by the autoimmune regulator (AIRE), an intra-nuclear regulating factor of gene expression highly active in medullary thymic epithelial cells (20,21) . This process leads to the acquisition of self-tolerance by the negative selection of CD4þCD8þ thymocyte subsets that are potentially autoreactive against self-antigens (22) .…”