Abstract
ABSTRACTWe previously established three mouse cell lines (Aire+TEC1, Aire+TEC2 and Aire+DC) from the medullary thymic epithelial cells (mTECs) and dendritic cells (mDCs). These cells constitutively expressed “autoimmune regulator (Aire) gene” and they exhibited various features of self antigen-presenting cells (self-APCs) present in the thymic medullary region.Here, we confirmed our previous observation that Aire+ thymic epithelial cells adhere to fresh thymocytes and kill them by inducing apoptosis, thus potentially reproducing in vitro some aspects of the negative selection of T cells in vivo. In this system, a single Aire+ cell appeared able to kill ∼30 thymocytes within 24 hrs. Moreover, we observed that ectopic expression of peripheral tissue-specific antigens (TSAs), and expression of several surface markers involved in mTEC development, increased as Aire+ cell density increases toward confluency. Thus, these Aire+ cells appear to behave like differentiating mTECs as if they pass through the developmental stages from intermediate state toward mature state. Surprisingly, an in vitro co-culture system consisting of Aire+ cells and fractionated sub-populations of fresh thymocytes implied the possible existence of two distinct subtypes of thymocytes (named as CD4+ killer and CD4− rescuer) that may determine the fate (dead or alive) of the differentiating Aire+mTECs. Thus, our in vitro co-culture system appears to mimic a part of “in vivo thymic crosstalk”.
Highlights
The mammalian thymus consists of two main compartments, cortex and medulla, that are composed of thymic epithelial cell (TEC) populations
It should be noted that ectopic expression of tissue-specific antigens (TSAs) genes in self-antigen-presenting cells (APCs) is regulated, at least in part, by a transcription factor AIRE that we previously found deficient in the patients with autoimmune disease APECED (Nagamine et al, 1997; Aaltonen et al, 1997)
All three autoimmune regulator (Aire)+ cell lines (Aire+TEC1, Aire+TEC2 and Aire+DC) consistently express endogenous Aire protein In our initial characterization study (Yamaguchi et al, 2011), expression of Aire mRNA was clearly detected in all three Aire+ cell lines (Aire+TEC1, TEC2 and DC) but endogenous Aire protein could not be detected, perhaps due to poor quality of polyclonal antibodies used
Summary
The mammalian thymus consists of two main compartments, cortex and medulla, that are composed of thymic epithelial cell (TEC) populations. The cortex is composed of cortical TECs (cTECs) and the medulla is composed of medullary TECs (mTECs). The cortical and medullary compartments are formed under precise cellular process ‘‘thymic crosstalk’’, which is a. Some cTECs expressing distinct major histocompatibility complex (MHC) promote positive selection of immature (CD42CD82) thymocytes that are differentiating to CD4+CD8+ double-positive (DP) thymocytes. The positively selected DP thymocytes in the cortex are relocated to medulla
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