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Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing, Michelle J

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Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing, Michelle J 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. This information is current as Hollander, Kenneth I. Weinberg, Jakub Tolar, Heather E. of September 28, 2021. Stefanski and Bruce R. Blazar J Immunol published online 29 October 2018 http://www.jimmunol.org/content/early/2018/10/28/jimmun ol.1800670 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 29, 2018, doi:10.4049/jimmunol.1800670 The Journal of Immunology Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho Yan Xing,*,1 Michelle J. Smith,*,†,1 Christine A. Goetz,*,† Ron T. McElmurry,* Sarah L. Parker,* Dullei Min,‡ Georg A. Hollander,x,{ Kenneth I. Weinberg,‡ Jakub Tolar,* Heather E. Stefanski,*,2 and Bruce R. Blazar*,†,2 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 thymo- poiesis 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2018, 201: 000–000. hymic aging is a major contributing factor to immuno- homeostatic oligoclonal expansion of T cells in the periphery logical senescence as the thymus begins to involute with (4, 5). These dynamic changes result in an increased susceptibil- T the onset of puberty, leading to a progressive defect in the ity to infections (6, 7), suboptimal responses to vaccines (8–12), ability to generate naive T cells (1, 2). The primary elements of and an increased risk to develop cancer and autoimmune diseases by guest on September 28, 2021 the thymic microenvironment affected by age-related involution (13–15). The age-related decline in thymopoietic activity (1) is are structural thymic epithelial cells (TECs). TECs are replaced by especially apparent in patients who have undergone chemotherapy adipocytes and peripheral lymphocytes, resulting in decreased (16) or allogeneic hematopoietic stem cell (HSC) transplantation thymopoietic activity and T cell selection (3). Consequently, both (17). The necessary preparative regimen with cytotoxic chemo- quantity and quality of the T cell repertoire are affected with therapy and/or radiation severely damages the thymus, the recovery decreased de novo T cell generation, which is compensated by a of which is extremely limited in aged individuals (18, 19). To study the process of aging in mice, Klotho-deficient (Kl/Kl) *Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic animals have been used, as they grow normally up to 3 wk of age Cancer Center, University of Minnesota, Minneapolis, MN 55455; †Center for Im- and then begin to show premature aging phenotypes (20). Klotho munology, University of Minnesota Medical School, Minneapolis, MN 55455; ‡Division of Stem Cell Transplantation and Regenerative Medicine, Department of encodes a b-glucuronidase–related molecule in two separate iso- Pediatrics, Stanford Medicine, Stanford University, Palo Alto, CA 94304; xDepart- forms, transmembrane and secreted; the transmembrane molecule { ment of Biomedicine, University of Basel, 4056 Basel, Switzerland; and Department serves as a coreceptor for fibroblast growth factor 23 (FGF23) by of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom transporting this cytokine to its receptor, FGFR1c, and thereby 1Y.X. and M.J.S. contributed equally to this work. regulating mineral metabolism (21–23). Klotho is expressed in the 2H.E.S. and B.R.B. contributed equally to this work. kidney and parathyroid gland, and the secreted form can also be found in the blood, cerebrospinal fluid, and urine (24). FGF23 ORCIDs: 0000-0003-2150-1448 (Y.X.); 0000-0002-8790-0874 (G.A.H.); 0000-0002- 0957-4380 (J.T.); 0000-0001-7527-9315 (H.E.S.); 0000-0002-9608-9841 (B.R.B.). suppresses phosphate reabsorption and vitamin D synthesis in the Received for publication May 11, 2018. Accepted for publication September 28, kidney, causing negative phosphate balance because of both its 2018. phosphaturic hormone function and its function as a counter- This work was supported by the National Institutes of Health Grants P01 CA065493, regulatory hormone for vitamin D (24). The secreted form of R01 AI081918, and 2P01 CA065493, and the Children’s Cancer Research Fund. Klotho inhibits insulin growth factor 1 signaling and confers in- Address correspondence and reprint requests to Dr. Bruce R. Blazar, University of creased resistance to oxidative stress (25–27). Mice transgenic for Minnesota, 420 Delaware Street, SE, Mayo Mail Code 109, Minneapolis, MN 55455. E-mail address: [email protected] Klotho live 20–30% longer than wild-type (WT) controls (28), Abbreviations used in this article: BM, bone marrow cell; cTEC, cortical TEC; whereas the protein’s absence results in an advanced aging syn- DN, double-negative; DP, double-positive; FGF23, fibroblast growth factor 23; drome resembling progeria. Multiple organs are affected in Kl/Kl HSC, hematopoietic stem cell; Kl/Kl, Klotho-deficient; mTEC, medullary TEC; SP, mice, resulting in growth retardation, pituitary abnormalities, ar- single-positive; TEC, thymic epithelial cell; Treg, regulatory T cell; WT, wild-type. teriosclerosis, ectopic calcification of various organs, osteoporosis, Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 skin atrophy, emphysema, and atrophy of both the genital organs www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800670 2 TEC SUPPORT OF THYMOPOIESIS DOES NOT REQUIRE Klotho and the thymus (20). Interestingly, mice that are FGF23 deficient pressure (30); and demonstrate an increased risk for stroke and or Kl/Kl have phenotypes similar to one another. These deficits coronary artery disease (31). Polymorphisms in KLOTHO (loss of can be alleviated by reversing the effects of hyperphosphatemia function) have been associated with an increased risk for osteo- either genetically or by diet, suggesting a link between aging and porosis and spondylosis (32), and reduced KLOTHO protein ex- phosphate (24). pression has been noted in patients with chronic renal failure (33). The Kl/Kl mouse model has provided insight into the process of Although the effects of Klotho deficiency on kidney develop- aging in humans. Indeed, human KLOTHO shares 86% amino ment and function, mineral metabolism, and bone maintenance are acid identity with its mouse ortholog (29). Individuals homozy- well studied in Kl/Kl mice, the direct effect of Klotho deficiency gous for KLOTHO variants that disrupt the molecule’s trafficking on the TECs is unknown. We therefore sought to determine and catalytic functions experience a decreased life expectancy whether the effects of Klotho on thymic aging are cell intrinsic or (29); have increased cardiovascular risk factors, such as elevated reflect a systemic metabolic consequence of a lack of the Klotho high-density lipoprotein cholesterol levels and high systolic blood protein. Downloaded from
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