Thymic epithelial cell support of thymopoiesis does not require Klotho

Yan Xing, Michelle J. Smith, Christine A. Goetz, Ron T. McElmurry, Sarah L. Parker, Dullei Min, Georg A. Hollander, Kenneth I. Weinberg, Jakub Tolar, Heather E. Stefanski, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10-100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D-deprived diet. We observed that a vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.

Original languageEnglish (US)
Pages (from-to)3320-3328
Number of pages9
JournalJournal of Immunology
Volume201
Issue number11
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grants P01 CA065493, R01 AI081918, and 2P01 CA065493, and the Children’s Cancer Research Fund.

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