Abstract
Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). TEC development and function are regulated by their epigenetic landscape, in which the repressive H3K27me3 epigenetic marks are catalyzed by polycomb repressive complex 2 (PRC2). Here we show that a TEC-targeted deficiency of PRC2 function results in a hypoplastic thymus with reduced ability to express antigens and select a normal repertoire of T cells. The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged. This alternative TEC development is associated with the generation of reduced TCR diversity. Hence, normal PRC2 activity and placement of H3K27me3 marks are required for TEC lineage differentiation and function and, in their absence, the thymus is unable to compensate for the loss of a normal TEC scaffold.
Highlights
Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC)
CTEC cellularity did not diminish in adolescent Eedfl/fl::β5tCre mice contrary to controls
The loss of EED in β5t-expressing TEC precursors and their progeny resulted in an absence of polycomb repressive complex 2 (PRC2) activity in practically all characteristics into separate cortical (cTECs) and the majority of mTEC
Summary
Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged This alternative TEC development is associated with the generation of reduced TCR diversity. Thymic epithelial cells (TECs), which can be categorized based on specific molecular, structural and functional characteristics into separate cortical (cTECs) and medullary (mTECs) lineages, are essential for this competence[1]. Both TEC lineages derive from a common epithelial precursor of endodermal origin[2,3] that expresses a range of cTEC-specific markers including the proteasome component β5t encoded by Psmb[114–7]. Compromised gene repression due to a loss of PRC2 activity[23] impairs tissue specification and maintenance, and results in early embryonic lethality[24]
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