Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho.

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.

• Authors: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 201 Issue 11 Pg. 3320-3328 (12 01 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 30373854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Vitamin D
• Fibroblast Growth Factors
• Glucuronidase
• Klotho Proteins

Topics

• Adoptive Transfer
• Aging (physiology)
• Aging, Premature (genetics)
• Animals
• Cells, Cultured
• Diet Therapy
• Epithelial Cells (physiology)
• Fibroblast Growth Factors (metabolism)
• Glucuronidase (genetics, metabolism)
• Klotho Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• T-Lymphocytes (physiology)
• Thymocytes (physiology)
• Thymus Gland (physiology, transplantation)
• Transplantation
• Vitamin D (metabolism)