IFN-λ Enhances Constitutive Expression of MHC Class I Molecules on Thymic Epithelial Cells

Abstract

Regulation of MHC class I (MHC I) expression has been studied almost exclusively in hematolymphoid cells. We report that thymic epithelial cells (TECs), particularly the medullary TECs, constitutively express up to 100-fold more cell surface MHC I proteins than epithelial cells (ECs) from the skin, colon, and lung. Differential abundance of cell surface MHC I in primary ECs is regulated via transcription of MHC I and of genes implicated in the generation of MHC I-binding peptides. Superior MHC I expression in TECs is unaffected by deletion of Ifnar1 or Ifngr1, but is lessened by deletion of Aire, Ifnlr1, Stat1, or Nlrc5, and is driven mainly by type III IFN produced by medullary TECs. Ifnlr1 2/2 mice show impaired negative selection of CD8 thymocytes and, at 9 mo of age, present autoimmune manifestations. Our study shows unanticipated variation in MHC I expression by ECs from various sites and provides compelling evidence that superior expression of MHC I in TECs is crucial for proper thymocyte education.

The Origin and Immune Recognition of Tumor-Specific Antigens

“…The problem here is that this atlas does not contain the MAP repertoire of all cell types. Thus, since most epithelial cells express lower levels of MHC molecules than hematopoietic cells [48,49], whole tissue extracts are enriched in hematopoietic relative to epithelial MAPs. Furthermore, several cell types in the organism are not present in numbers sufficient for mass spectrometry analyses.…”

“…Hence, when we identify aeTSA candidates, we evaluate whether its coding transcript is found in normal tissues from the GTEx database (https://gtexportal.org/home/) or in our datasets of medullary thymic epithelial cells [26]. We believe that inclusion of medullary thymic epithelial cells in the "negative controls" is important for three reasons: (i) they orchestrate central immune tolerance [67], (ii) they express much higher levels of MHC I molecules than other epithelial cell types [49], and (iii) they promiscuously express more genes than other types of somatic cells [68,69]. Promiscuous gene expression in medullary thymic epithelial cells involves not only classic genes, but also other genomic regions such as endogenous retroelements [26].…”

“…The most critical positive co-stimulatory signal is provided by CD28 upon interaction with its ligands of the B7 family (CD80/86) on antigen-presenting cells (APCs) [72]. Tumor cells are poor APCs: they express no/low levels of CD28 ligands, and carcinomas (90% of cancers) derive from epithelial cells expressing 10 to 100-fold less MHC I molecules than DCs [49]. As a result, tumor cells are inefficient at directly priming naïve CD8 T cells, and activation of T cells against tumor antigens depends on cross-presentation by professional APCs [73].…”

The Origin and Immune Recognition of Tumor-Specific Antigens

“…The problem here is that this atlas does not contain the MAP repertoire of all cell types. Thus, since most epithelial cells express lower levels of MHC molecules than hematopoietic cells [47,48], whole tissue extracts are enriched in hematopoietic relative to epithelial MAPs. Furthermore, several cell types in the organism are not present in numbers sufficient for MS analyses.…”

“…Hence, when we identify aeTSA candidates, we evaluate whether its coding transcript is found in normal tissues from the GTEx database (https://gtexportal.org/home/) or in our datasets of mTECs [26]. We believe that inclusion of mTECs in the "negative controls" is important for three reasons: i) they orchestrate central immune tolerance [66], ii) they express much higher levels of MHC I molecules than other epithelial cell types [48], and iii) they promiscuously express more genes than other types of somatic cells [67,68].…”