Abstract
While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall’s corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall’s corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance.
Highlights
The thymus is a primary immune organ required for T cell development
Post-Aire Populations and Pro-Inflammatory Signaling derived signal strength [2], which in turn depends on the availability and affinity of self-peptides in the thymus and is regulated by a range of co-stimulatory molecules expressed on antigen presenting cells (APC) [1, 2]
As the medullary thymic epithelial cells (mTEC)-derived exosomes have been shown to carry the keratinocyte-specific autoantigens DSG-1, DSG-3 as well KRT5 and KRT14 [54], the data is compatible with the view suggesting that even after losing their MHCII expression, the post-Aire mTECs and Hassall’s corpuscles (HCs) may actively contribute to the induction of central tolerance by synthesis and exocytosis of self-proteins for cross-presentation
Summary
The thymus is a primary immune organ required for T cell development. The maturation process of the developing T cells, the thymocytes, involves somatic recombinations to randomly generate functional T cell receptors that in principle can recognize all possible antigenic determinants [reviewed in [1]]. There is an increasing amount of evidence that at least in mice the post-Aire cells and HCs may contribute to the tonic inflammatory signaling in the thymic medulla, which in turn may play a role in the induction of central tolerance. As the mTEC-derived exosomes have been shown to carry the keratinocyte-specific autoantigens DSG-1, DSG-3 as well KRT5 and KRT14 [54], the data is compatible with the view suggesting that even after losing their MHCII expression, the post-Aire mTECs and HCs may actively contribute to the induction of central tolerance by synthesis and exocytosis of self-proteins for cross-presentation. As we saw an upregulation of the TLR4 binding related processes at the late stages of mTEC differentiation (Figure 1), our data strongly suggest that post-Aire mTECs and HCs may play a role in the induction of tonic inflammatory signals by constitutive expression of the endogenous TLR4 agonist, S100A8/A9
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