RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla.
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4(+)3(-) inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4(+)3(-) cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire(+) mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80(-)Aire(-) mTEC progenitors into CD80(+)Aire(+) mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire(+) mTECs and highlight a previously unrecognized role for CD4(+)3(-)RANKL(+) inducer cells in intrathymic self-tolerance.
Rossi
Simona W
SW
Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, B15 2TT Birmingham, UK.
Kim
Mi-Yeon
MY
Leibbrandt
Andreas
A
Parnell
Sonia M
SM
Jenkinson
William E
WE
Glanville
Stephanie H
SH
McConnell
Fiona M
FM
Scott
Hamish S
HS
Penninger
Josef M
JM
Jenkinson
Eric J
EJ
Lane
Peter J L
PJ
Anderson
Graham
G
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000096927:AIRE Protein
D017931:DNA Primers; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D000096927:AIRE Protein; C505687:Tnfrsf11a protein, mouse