Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho

Abstract

<p class="first" id="P1">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 <i>Klotho</i>, an anti-aging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of <i>Klotho</i> in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using <i>Klotho</i>-deficient mice. At 8 weeks of age, <i>Klotho</i>-deficient 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 TEC. To address a cell-autonomous role for <i>Klotho</i> in TEC biology, we implanted neonatal thymi from <i>Klotho</i>-deficient and -sufficient mice into athymic hosts. <i>Klotho</i>-deficient thymus grafts supported thymopoiesis equivalently to <i>Klotho</i>-sufficient thymus transplants, indicating that <i>Klotho</i> is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally-irradiated hosts given <i>Klotho</i>-deficient or WT bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating <i>Klotho</i> is not inherently essential for peripheral T cell reconstitution. Because <i>Klotho</i>-deficient mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in <i>Klotho</i>-deficient mice fed with vitamin D-deprived diet. We observed that vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-week-old <i>Klotho</i>-deficient mice. Taken together, our data suggests that <i>Klotho</i>-deficiency causes thymic involution via systemic effects that include high active vitamin D levels. </p>