Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution.
Age-related thymic involution may be triggered by gene expression changes in lymphohematopoietic and/or nonhematopoietic thymic epithelial cells (TECs). The role of epithelial cell-autonomous gene FoxN1 may be involved in the process, but it is still a puzzle because of the shortage of evidence from gradual loss-of-function and exogenous gain-of-function studies. Using our recently generated loxP-floxed-FoxN1(fx) mouse carrying the ubiquitous CreER(T) (uCreER(T)) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreER(T)-fx/fx mice showed an accelerated age-related thymic involution owing to progressive loss of FoxN1(+) TECs. The thymic aging phenotypes were clearly observable as early as at 3-6 months of age, resembling the naturally aged (18-22-month-old) murine thymus. By intrathymically supplying aged wild-type mice with exogenous FoxN1-cDNA, thymic involution and defective peripheral CD4(+) T-cell function could be partially rescued. The results support the notion that decline of a single epithelial cell-autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers age-related thymic involution in mice.
Department of Biomedical Research, University of Texas Health Science Center at Tyler, 75708, USA.
Liguang
L
Sun
Jianfei
J
Guo
Robert
R
Brown
Takashi
T
Amagai
Yong
Y
Zhao
Dong-Ming
DM
Su
D000375:Aging; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009929:Organ Size; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C090140:Whn protein