Identification of novel thymic epithelial cell subsets whose differentiation is regulated by RANKL and Traf6.
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.
Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, United States of America.
Nichole M
NM
Danzl
Department of Medicine, Division of Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Seihwan
S
Jeong
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Yongwon
Y
Choi
Department of Medicine, Division of Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Konstantina
K
Alexandropoulos
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D000951:Antigens, Neoplasm / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053245:RANK Ligand / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000096927:AIRE Protein
D000951:Antigens, Neoplasm; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D000096927:AIRE Protein