Abstract
Thymic epithelial cells (TECs) are critical for the normal development and function of the thymus. Here, we examined the developmental stages of TECs using quantitative assessment of the cortical and medullary markers Keratin 5 and Keratin 8 (K5 and K8) respectively, in normal and gain/loss of function mutant animals. Gain of function mice overexpressed RANKL in T cells, whereas loss of function animals lacked expression of Traf6 in TECs (Traf6ΔTEC). Assessment of K5 and K8 expression in conjunction with other TEC markers in wild type mice identified novel cortical and medullary TEC populations, expressing different combinations of these markers. RANKL overexpression led to expansion of all medullary TECs (mTECs) and enlargement of the thymic medulla. This in turn associated with a block in thymocyte development and loss of CD4+CD8+, CD4+ and CD8+ thymocytes. In contrast, Traf6 deletion inhibited the production of most TEC populations including cortical TECs (cTECs), defined by absence of UEA-1 binding and LY51 expression, but had no apparent effect on thymocyte development. These results reveal a large degree of heterogeneity within the TEC compartment and the existence of several populations exhibiting concomitant expression of cortical, medullary and epithelial markers and whose production is regulated by RANKL and Traf6.
Highlights
Normal development of T cells in the thymus depends on interactions between the T cell receptors (TCRs) of developing thymocytes and peptide antigens presented by cortical and medullary thymic epithelial cells
Consistent with the results that receptor activator of NFkB ligand (RANKL) overexpression led to expansion of medullary Thymic Epithelial Cell (TEC) (mTECs), we found increased staining with MHCII, ulex europeus agglutinin-1 (UEA-1) and Aire in the thymi of RANKL-Tg mice compared to wild type controls (Figure S4A and B, bottom two panels and data not shown)
A total of nine populations were identified which were classified as mTECs and minor cortical TECs (cTECs) based on UEA-1 binding and/or expression of the cortical marker LY51 and Keratin 8 (K8)/Keratin 5 (K5)
Summary
Normal development of T cells in the thymus depends on interactions between the T cell receptors (TCRs) of developing thymocytes and peptide antigens presented by cortical and medullary thymic epithelial cells (cTECs and mTECs respectively). Self-antigen presentation on cTECs regulates thymocyte positive selection, while self-antigens expressed on mTECs mediate negative selection of autoreactive T cells [1]. Over the past several years mTECs have emerged as important regulators of T cell tolerance by ectopically expressing a wide range of tissuespecific antigens (TSAs) [2]. Mutations in the aire gene in humans result in the development of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome [9,10,11], whereas Aire deletion in mice leads to autoantibody production against and inflammatory infiltrates in multiple tissues [8]. In addition to Aire, genetic mutations that affect the development of mTECs have varied effects on mTEC function and autoimmunity. Deletion or mutation of RelB [12], the tumor necrosis factor receptor-associated factor 6 (Traf6) [13], NFkB-
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