Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels.
The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80(hi) mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and -independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance.
Derbinski
Jens
J
Division of Developmental Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Gäbler
Jana
J
Brors
Benedikt
B
Tierling
Sascha
S
Jonnakuty
Sunitha
S
Hergenhahn
Manfred
M
Peltonen
Leena
L
Walter
Jörn
J
Kyewski
Bruno
B
D000818:Animals; D001324:Autoantigens; D018122:B7-1 Antigen / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family; D009115:Muridae; D011247:Pregnancy; D017634:Self Tolerance; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D000096927:AIRE Protein
D001324:Autoantigens; D018122:B7-1 Antigen; D018076:DNA, Complementary; D007334:Insulin-Like Growth Factor I; D014157:Transcription Factors; D000096927:AIRE Protein