Figure 3. Topological aspects of ‘promiscuous gene expression’ and direct versus indirect presentation of TRAs.

(a) Ttissue-restricted antigens (TRAs) are expressed by only a small subset of mTECs at any given point in time: In-situ hybridization of a section through an entire thymic lobe for Aire mRNA expression (left) shows that Aire-expressing cells are densely packed in medullary regions. By contrast, transcripts of three representative TRAs (dermakine, Dmkn; Serin protease inhibitor kazal type 3, Spink3; chloride channel calcium activated 3; Clca3) are only detectable in very few cells that are scattered throughout medullary areas (dotted lines). (b) Tolerogenic presentation of TRAs that are expressed by few mTECs may occur in two not mutually exclusive ways: (left) direct presentation by TRA-expressing mTECs themselves, whereby efficient endogenous MHC class II-loading by mTECs in conjunction with serial ‘scanning’ of multiple medullary APCs by thymocytes increases the likelihood of cognate self-antigen interactions. (middle) ‘Antigen handover’ to neighbouring cDCs may extend the area of tolerogenic presentation in a mosaic fashion beyond the topologically restricted expression pattern (right). The mechanistic details of this ‘directional antigen transfer’ transfer remain to be established. It is conceivable that TRAs are released or shed in soluble form to be subsequently captured and processed by cDCs for presentation on MHC class I or II. Apoptosis of terminally differentiated mTECs may lead to the release of apoptotic fragments that can also transfer mTEC-derived self-antigens to cDCs. In addition, functional peptide-MHC ligands are unidirectionally translocated from mTECs to DCs ^{42, 118}.