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Review

Role of thymus in health and disease

, , , , &
Pages 347-363 | Received 15 Feb 2022, Accepted 04 Apr 2022, Published online: 20 May 2022

References

  • Sinkovskaya ES, Abuhamad A. The Fetal Thymus: Fetal Cardiology. Boca Raton, FL: CRC Press; 2018: 490–513.
  • Hammar JA. The new views as to the morphology of the thymus gland and their bearing on the problem of the function of the thymus. Endocrinology. 1921;5(5):543–573. doi:10.1210/endo-5-5-543.
  • Ribatti D. Hans Selye and his studies on the role of mast cells in calciphylaxis and calcergy. Inflamm Res. 2019;68(2):177–180. doi:10.1007/s00011-018-1199-7.
  • Miller JF. Immunological function of the thymus. Lancet. 1961;2(7205):748–749. doi:10.1016/S0140-6736(61)90693-6.
  • MacDonald HR, Schneider R, Lees RK, et al. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988;332(6159):40–45. doi:10.1038/332040a0.
  • Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4 + 8+ thymocytes. Nature. 1988;333(6175):742–746. doi:10.1038/333742a0.
  • Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987;49(2):273–280. doi:10.1016/0092-8674(87)90568-X.
  • Ohki H, Martin C, Corbel C, Coltey M, Le Douarin NM. Tolerance induced by thymic epithelial grafts in birds. Science. 1987;237(4818):1032–1035. doi:10.1126/science.3616623.
  • Domínguez-Gerpe L, Rey-Méndez M. Evolution of the thymus size in response to physiological and random events throughout life. Microsc Res Tech. 2003;62(6):464–476. doi:10.1002/jemt.10408.
  • Blackburn CC, Manley NR. Developing a new paradigm for thymus organogenesis. Nat Rev Immunol. 2004;4(4):278–289. doi:10.1038/nri1331.
  • Bódi I, H-Minkó K, Prodán Z, Nagy N, Oláh I. [Structure of the thymus at the beginning of the 21th century]. Orv Hetil. 2019;160(5):163–171. doi:10.1556/650.2019.31224.
  • Haley PJ. Species differences in the structure and function of the immune system. Toxicology. 2003;188(1):49–71. doi:10.1016/S0300-483X(03)00043-X.
  • Kurd N, Robey EA. T-cell selection in the thymus: a spatial and temporal perspective. Immunol Rev. 2016;271(1):114–126. doi:10.1111/imr.12398.
  • Gordon J, Manley NR. Mechanisms of thymus organogenesis and morphogenesis. Development. 2011;138(18):3865–3878. doi:10.1242/dev.059998.
  • Abramson J, Anderson G. Thymic Epithelial Cells. Annu Rev Immunol. 2017;35:85–118. doi:10.1146/annurev-immunol-051116-052320.
  • Nitta T, Takayanagi H. Non-epithelial thymic stromal cells: unsung heroes in thymus organogenesis and T cell development. Front Immunol. 2020;11:620894–620894. doi:10.3389/fimmu.2020.620894.
  • Takahama Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol. 2006;6(2):127–135. doi:10.1038/nri1781.
  • Montecino-Rodriguez E, Dorshkind K. Evolving patterns of lymphopoiesis from embryogenesis through senescence. Immunity. 2006;24(6):659–662. doi:10.1016/j.immuni.2006.06.001.
  • Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007;42(5):400–406. doi:10.1016/j.exger.2006.11.016.
  • Steinmann GG, Klaus B, Müller-Hermelink HK. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol. 1985;22(5):563–575. doi:10.1111/j.1365-3083.1985.tb01916.x.
  • Gray DHD, Seach N, Ueno T, et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood. 2006;108(12):3777–3785. doi:10.1182/blood-2006-02-004531.
  • Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol. 2005;175(5):2982–2993. doi:10.4049/jimmunol.175.5.2982.
  • Min H, Montecino-Rodriguez E, Dorshkind K. Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol. 2004;173(1):245–250. doi:10.4049/jimmunol.173.1.245.
  • Montecino-Rodriquez E, Min H, Dorshkind K. Reevaluating current models of thymic involution. Semin Immunol. 2005;17(5):356–361. doi:10.1016/j.smim.2005.05.006.
  • Takeoka Y, Chen SY, Yago H, et al. The murine thymic microenvironment: changes with age. Int Arch Allergy Immunol. 1996;111(1):5–12. doi:10.1159/000237337.
  • Taub DD, Longo DL. Insights into thymic aging and regeneration. Immunol Rev. 2005;205:72–93. doi:10.1111/j.0105-2896.2005.00275.x.
  • Mackall CL, Punt JA, Morgan P, Farr AG, Gress RE. Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution. Eur. J. Immunol. 1998;28(6):1886–1893. doi:10.1002/(SICI)1521-4141(199806)28:06<1886::AID-IMMU1886>3.0.CO;2-M.
  • Griffith AV, Fallahi M, Venables T, Petrie HT. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell. 2012;11(1):169–177. doi:10.1111/j.1474-9726.2011.00773.x.
  • Reis MD, Csomos K, Dias LP, et al. Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation. Immun Ageing. 2015;12:18. doi:10.1186/s12979-015-0045-9.
  • Itoi M, Kawamoto H, Katsura Y, Amagai T. Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage. Int Immunol. 2001;13(9):1203–1211. doi:10.1093/intimm/13.9.1203.
  • Žuklys S, Handel A, Zhanybekova S, et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat Immunol. 2016;17(10):1206–1215. doi:10.1038/ni.3537.
  • Chen L, Xiao S, Manley NR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 2009;113(3):567–574. doi:10.1182/blood-2008-05-156265.
  • Garfin PM, Min D, Bryson JL, et al. Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. J Exp Med. 2013;210(6):1087–1097. doi:10.1084/jem.20121716.
  • Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A. 1998;95(20):11822–11827. doi:10.1073/pnas.95.20.11822.
  • Klug DB, Crouch E, Carter C, Coghlan L, Conti CJ, Richie ER. Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial and T cell development. J Immunol. 2000;164(4):1881–1888. doi:10.4049/jimmunol.164.4.1881.
  • Erickson M, Morkowski S, Lehar S, et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood. 2002;100(9):3269–3278. doi:10.1182/blood-2002-04-1036.
  • Zamisch M, Moore-Scott B, Su DM, Lucas PJ, Manley N, Richie ER. Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J Immunol. 2005;174(1):60–67. doi:10.4049/jimmunol.174.1.60.
  • Ribeiro AR, Rodrigues PM, Meireles C, Di Santo JP, Alves NL. Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J Immunol. 2013;191(3):1200–1209. doi:10.4049/jimmunol.1203042.
  • Yang H, Youm YH, Sun Y, et al. Axin expression in thymic stromal cells contributes to an age-related increase in thymic adiposity and is associated with reduced thymopoiesis independently of ghrelin signaling. J Leukoc Biol. 2009;85(6):928–938. doi:10.1189/jlb.1008621.
  • Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211(2):144–156. doi:10.1002/path.2104.
  • Conboy IM, Rando TA. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle. 2012;11(12):2260–2267. doi:10.4161/cc.20437.
  • Ki S, Park D, Selden HJ, et al. Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution. Cell Rep. 2014;9(1):402–415. doi:10.1016/j.celrep.2014.08.070.
  • Baran-Gale J, Morgan MD, Maio S, et al. Ageing compromises mouse thymus function and remodels epithelial cell differentiation. Elife. 2020;9:e56221. doi:10.7554/eLife.56221.
  • Boehm T, Scheu S, Pfeffer K, Bleul CC. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med. 2003;198(5):757–769. doi:10.1084/jem.20030794.
  • Akiyama T, Shimo Y, Yanai H, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29(3):423–437. doi:10.1016/j.immuni.2008.06.015.
  • Bichele R, Kisand K, Peterson P, Laan M. TNF superfamily members play distinct roles in shaping the thymic stromal microenvironment. Mol Immunol. 2016;72:92–102. doi:10.1016/j.molimm.2016.02.015.
  • St-Pierre C, Morgand E, Benhammadi M, et al. Immunoproteasomes Control the Homeostasis of Medullary Thymic Epithelial Cells by Alleviating Proteotoxic Stress. Cell Rep. 2017;21(9):2558–2570. doi:10.1016/j.celrep.2017.10.121.
  • Lomada D, Liu B, Coghlan L, Hu Y, Richie ER. Thymus medulla formation and central tolerance are restored in IKKalpha-/- mice that express an IKKalpha transgene in keratin 5+ thymic epithelial cells. J Immunol. 2007;178(2):829–837. doi:10.4049/jimmunol.178.2.829.
  • Burkly L, Hession C, Ogata L, et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature. 1995;373(6514):531–536. doi:10.1038/373531a0.
  • Lomada D, Jain M, Bolner M, et al. Stat3 signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet. 2016;12(1):e1005777. doi:10.1371/journal.pgen.1005777.
  • Shen H, Ji Y, Xiong Y, et al. Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice. Proc Natl Acad Sci U S A. 2019;116(38):19090–19097. doi:10.1073/pnas.1901056116.
  • Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408(6809):239–247. doi:10.1038/35041687.
  • Davalli P, Mitic T, Caporali A, Lauriola A, D’Arca D. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid Med Cell Longev. 2016;(2016):3565127. doi:10.1155/2016/3565127.
  • Singh MK, Yadav SS, Gupta V, Khattri S. Immunomodulatory role of Emblica officinalis in arsenic induced oxidative damage and apoptosis in thymocytes of mice. BMC Complement Altern Med. 2013;13:193. doi:10.1186/1472-6882-13-193.
  • Wang Y, Jiang L, Li Y, Luo X, He J. Effect of different selenium supplementation levels on oxidative stress, cytokines, and immunotoxicity in chicken thymus. Biol Trace Elem Res. 2016;172(2):488–495. doi:10.1007/s12011-015-0598-7.
  • Wei X, Su F, Su X, Hu T, Hu S. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia. 2012;83(4):636–642. doi:10.1016/j.fitote.2012.01.006.
  • Li YN, Guo Y, Xi MM, et al. Saponins from Aralia taibaiensis attenuate D-galactose-induced aging in rats by activating FOXO3a and Nrf2 pathways. Oxid Med Cell Longev. 2014;2014:320513. (); doi:10.1155/2014/320513.
  • Pinto M, Pickrell AM, Wang X, et al. Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner. Cell Death Differ. 2017;24(2):288–299. doi:10.1038/cdd.2016.123.
  • Barbouti A, Evangelou K, Pateras IS, et al. In situ evidence of cellular senescence in thymic epithelial cells (TECs) during human thymic involution. Mech Ageing Dev. 2019;177:88–90. doi:10.1016/j.mad.2018.02.005.
  • Barbouti A, Vasileiou P, Evangelou K, et al. Implications of oxidative stress and cellular senescence in age-related thymus involution. Oxid Med Cell Longev. 2020;2020:7986071. doi:10.1155/2020/7986071.
  • Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology. 2001;142(3):1278–1283. doi:10.1210/endo.142.3.8032.
  • Gui J, Morales AJ, Maxey SE, et al. MCL1 increases primitive thymocyte viability in female mice and promotes thymic expansion into adulthood. Int Immunol. 2011;23(10):647–659. doi:10.1093/intimm/dxr073.
  • Sutherland JS, Goldberg GL, Hammett MV, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol. 2005;175(4):2741–2753. doi:10.4049/jimmunol.175.4.2741.
  • Bugnon C, Maurat JP, Lenys D, Moreau N, Rousselet F. Study of the cytologic origin of thyrocalcitonin in rats with hypervitaminosis D. C R Seances Soc Biol Fil. 1967;161(12):2363–2366.
  • Dumont-Lagacé M, St-Pierre C, Perreault C. Sex hormones have pervasive effects on thymic epithelial cells. Sci Rep. 2015;5:12895. doi:10.1038/srep12895.
  • Klug DB, Carter C, Gimenez-Conti IB, Richie ER. Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol. 2002;169(6):2842–2845. doi:10.4049/jimmunol.169.6.2842.
  • Zoller AL, Kersh GJ. Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes. J Immunol. 2006;176(12):7371–7378. doi:10.4049/jimmunol.176.12.7371.
  • Rossi SW, Kim MY, Leibbrandt A, et al. RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007;204(6):1267–1272. doi:10.1084/jem.20062497.
  • Paolino M, Koglgruber R, Cronin S, et al. RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy. Nature. 2021;589(7842):442–447. doi:10.1038/s41586-020-03071-0.
  • Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009;27:287–312. doi:10.1146/annurev.immunol.25.022106.141532.
  • Morimoto J, Nishikawa Y, Kakimoto T, et al. Aire controls in trans the production of medullary thymic epithelial cells expressing Ly-6C/Ly-6G. J Immunol. 2018;201(11):3244–3257. doi:10.4049/jimmunol.1800950.
  • Aschenbrenner K, D’Cruz LM, Vollmann EH, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire + medullary thymic epithelial cells. Nat Immunol. 2007;8(4):351–358. doi:10.1038/ni1444.
  • Cowan JE, Parnell SM, Nakamura K, et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J Exp Med. 2013;210(4):675–681. doi:10.1084/jem.20122070.
  • Roberts NA, White AJ, Jenkinson WE, et al. Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium. Immunity. 2012;36(3):427–437. doi:10.1016/j.immuni.2012.01.016.
  • Shores EW, Van Ewijk W, Singer A. Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur J Immunol. 1991;21(7):1657–1661. doi:10.1002/eji.1830210711.
  • Surh CD, Ernst B, Sprent J. Growth of epithelial cells in the thymic medulla is under the control of mature T cells. J Exp Med. 1992;176(2):611–616. doi:10.1084/jem.176.2.611.
  • Nasreen M, Ueno T, Saito F, Takahama Y. In vivo treatment of class II MHC-deficient mice with anti-TCR antibody restores the generation of circulating CD4 T cells and optimal architecture of thymic medulla. J Immunol. 2003;171(7):3394–3400. doi:10.4049/jimmunol.171.7.3394.
  • Palmer DB, Viney JL, Ritter MA, Hayday AC, Owen MJ. Expression of the alpha beta T-cell receptor is necessary for the generation of the thymic medulla. Dev Immunol. 1993;3(3):175–179. doi:10.1155/1993/56290.
  • Kajiura F, Sun S, Nomura T, et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol. 2004;172(4):2067–2075. doi:10.4049/jimmunol.172.4.2067.
  • Jenkinson SR, Williams JA, Jeon H, et al. TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development. Proc Natl Acad Sci U S A. 2013;110(52):21107–21112. doi:10.1073/pnas.1314859111.
  • Perniola R. Twenty Years of AIRE. Front Immunol. 2018;9:98.
  • Ramsey C, Winqvist O, Puhakka L, et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet. 2002;11(4):397–409. doi:10.1093/hmg/11.4.397.
  • Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298(5597):1395–1401. doi:10.1126/science.1075958.
  • Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat Immunol. 2003;4(4):350–354. doi:10.1038/ni906.
  • Oh J, Wang W, Thomas R, Su DM. Capacity of tTreg generation is not impaired in the atrophied thymus. PLoS Biol. 2017;15(11):e2003352. doi:10.1371/journal.pbio.2003352.
  • Gardner JM, Metzger TC, McMahon EJ, et al. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4+ T cells. Immunity. 2013;39(3):560–572. doi:10.1016/j.immuni.2013.08.005.
  • Cepeda S, Cantu C, Orozco S, et al. Age-associated decline in Thymic B cell expression of aire and aire-dependent self-antigens. Cell Rep. 2018;22(5):1276–1287. doi:10.1016/j.celrep.2018.01.015.
  • Flores KG, Li J, Hale LP. B cells in epithelial and perivascular compartments of human adult thymus. Hum Pathol. 2001;32(9):926–934. doi:10.1053/hupa.2001.27106.
  • Almaghrabi S, Azzouz M, Ahnini RT. AAV9-mediated AIRE gene delivery clears circulating antibodies and tissue T-cell infiltration in a mouse model of autoimmune polyglandular syndrome type-1. Clin Transl Immunology. 2020;9:e1166.
  • Aharoni R, Aricha R, Eilam R, et al. Age dependent course of EAE in Aire-/- mice. J Neuroimmunol. 2013;262(1-2):27–34. doi:10.1016/j.jneuroim.2013.06.001.
  • Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. The cellular mechanism of Aire control of T cell tolerance. Immunity. 2005;23(2):227–239. doi:10.1016/j.immuni.2005.07.005.
  • Haljasorg U, Bichele R, Saare M, et al. A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. Eur J Immunol. 2015;45(12):3246–3256. doi:10.1002/eji.201545928.
  • Kadouri N, Nevo S, Goldfarb Y, Abramson J. Thymic epithelial cell heterogeneity: TEC by TEC. Nat Rev Immunol. 2020;20(4):239–253. doi:10.1038/s41577-019-0238-0.
  • Tomofuji Y, Takaba H, Suzuki HI, et al. Chd4 choreographs self-antigen expression for central immune tolerance. Nat Immunol. 2020;21(8):892–901. doi:10.1038/s41590-020-0717-2.
  • Donnenberg AD, Margolick JB, Beltz LA, Donnenberg VS, Rinaldo CR. Jr., Apoptosis parallels lymphopoiesis in bone marrow transplantation and HIV disease. Res Immunol. 1995;146(1):11–21. doi:10.1016/0923-2494(96)80236-7.
  • Duan X, Lu J, Zhou K, et al. NK-cells are involved in thymic atrophy induced by influenza A virus s infection. J Gen Virol. 2015;96(11):3223–3235. doi:10.1099/jgv.0.000276.
  • Liu B, Zhang X, Deng W, et al. Severe influenza A(H1N1)pdm09 infection induces thymic atrophy through activating innate CD8(+)CD44(hi) T cells by upregulating IFN-γ. Cell Death Dis. 2014;5:e1440. doi:10.1038/cddis.2014.323.
  • Hayasaka D, Ennis FA, Terajima M. Pathogeneses of respiratory infections with virulent and attenuated vaccinia viruses. Virol J. 2007;4:22. doi:10.1186/1743-422X-4-22.
  • Nunes-Alves C, Nobrega C, Behar SM, Correia-Neves M. Tolerance has its limits: how the thymus copes with infection. Trends Immunol. 2013;34(10):502–510. doi:10.1016/j.it.2013.06.004.
  • Beltz L. Thymic involution and HIV progression. Immunol Today. 1999;20(9):429. doi:10.1016/S0167-5699(99)01516-9.
  • Ye P, Kirschner DE, Kourtis AP. The thymus during HIV disease: role in pathogenesis and in immune recovery. Curr HIV Res. 2004;2(2):177–183. doi:10.2174/1570162043484898.
  • Stephens EB, McCormick C, Pacyniak E, et al. Deletion of the vpu Sequences prior to the env in a simian-human immunodeficiency virus results in enhanced Env precursor synthesis but is less pathogenic for pig-tailed macaques. Virology. 2002;293(2):252–261. doi:10.1006/viro.2001.1244.
  • Clark R. The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr Rev. 1997;18(2):157–179. doi:10.1210/edrv.18.2.0296.
  • Napolitano LA, Lo JC, Gotway MB, et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS. 2002;16(8):1103–1111.
  • Douek DC, Koup RA, McFarland RD, Sullivan JL, Luzuriaga K. Effect of HIV on thymic function before and after antiretroviral therapy in children. J Infect Dis. 2000;181(4):1479–1482. doi:10.1086/315398.
  • Napolitano LA, Schmidt D, Gotway MB, et al. Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest. 2008;118(3):1085–1098.
  • Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11(5):330–342. doi:10.1038/nri2970.
  • Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119(4):997–1007.
  • Lévy Y, Sereti I, Tambussi G, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012;55(2):291–300. doi:10.1093/cid/cis383.
  • Lins MP, Smaniotto S. Potential impact of SARS-CoV-2 infection on the thymus. Can J Microbiol. 2021;67(1):23–28. doi:10.1139/cjm-2020-0170.
  • Wang W, Thomas R, Oh J, Su DM. Thymic aging may be associated with COVID-19 pathophysiology in the elderly. Cells. 2021;10(3):628. doi:10.3390/cells10030628.
  • Peng Y, Mentzer AJ, Liu G, ISARIC4C Investigators, et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol. 2020;21(11):1336–1345. doi:10.1038/s41590-020-0782-6.
  • Kellogg C, Equils O. The role of the thymus in COVID-19 disease severity: implications for antibody treatment and immunization. Hum Vaccin Immunother. 2021;17(3):638–643. doi:10.1080/21645515.2020.1818519.
  • Ayhan SG, Turgut E, Oluklu D, et al. Influence of Covid-19 infection on fetal thymus size after recovery. J Perinat Med. 2022;50(2):139–143. doi:10.1515/jpm-2021-0322.
  • Rehman S, Majeed T, Ansari MA, Ali U, Sabit H, Al-Suhaimi EA. Current scenario of COVID-19 in pediatric age group and physiology of immune and thymus response. Saudi J Biol Sci. 2020;27(10):2567–2573. doi:10.1016/j.sjbs.2020.05.024.
  • von Tresckow J, von Tresckow B, Reinhardt HC, Herrmann K, Berliner C. Thymic hyperplasia after mRNA based COVID-19 vaccination. Radiol Case Rep. 2021;16(12):3744–3745. doi:10.1016/j.radcr.2021.08.050.
  • Ballman M, Swift S, Mullenix C, et al. Tolerability of coronavirus disease 2019 vaccines, BNT162b2 and mRNA-1273, in patients with thymic epithelial tumors. JTO Clin Res Rep. 2021;2(10):100229. doi:10.1016/j.jtocrr.2021.100229.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi:10.3322/caac.21442.
  • Hsu T. Educational initiatives in geriatric oncology - Who, why, and how? J Geriatr Oncol. 2016;7(5):390–396. doi:10.1016/j.jgo.2016.07.013.
  • White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Henley SJ. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med. 2014;46(3 Suppl 1):S7–S15. doi:10.1016/j.amepre.2013.10.029.
  • Lian J, Yue Y, Yu W, Zhang Y. Immunosenescence: a key player in cancer development. J Hematol Oncol. 2020;13(1):151. doi:10.1186/s13045-020-00986-z.
  • Durgeau A, Virk Y, Corgnac S, Mami-Chouaib F. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front Immunol. 2018;9:14.
  • Godfrey DI, Koay HF, McCluskey J, Gherardin NA. The biology and functional importance of MAIT cells. Nat Immunol. 2019;20(9):1110–1128. doi:10.1038/s41590-019-0444-8.
  • Hale JS, Boursalian TE, Turk GL, Fink PJ. Thymic output in aged mice. Proc Natl Acad Sci U S A. 2006;103(22):8447–8452. doi:10.1073/pnas.0601040103.
  • Petrie HT. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol Rev. 2002;189:8–19. doi:10.1034/j.1600-065x.2002.18902.x.
  • Khan IS, Mouchess ML, Zhu ML, et al. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med. 2014;211(5):761–768. doi:10.1084/jem.20131889.
  • Sharma S, Dominguez AL, Lustgarten J. High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol. 2006;177(12):8348–8355. doi:10.4049/jimmunol.177.12.8348.
  • Wang W, Thomas R, Sizova O, Su D-M. Thymic function associated with cancer development, relapse, and antitumor immunity: a mini-review. Front Immunol. 2020;11:773–773. doi:10.3389/fimmu.2020.00773.
  • Zhao L, Sun L, Wang H, Ma H, Liu G, Zhao Y. Changes of CD4 + CD25 + Foxp3+ regulatory T cells in aged Balb/c mice. J Leukoc Biol. 2007;81(6):1386–1394. doi:10.1189/jlb.0506364.
  • Garg SK, Delaney C, Toubai T, et al. Aging is associated with increased regulatory T-cell function. Aging Cell. 2014;13(3):441–448. doi:10.1111/acel.12191.
  • Pan XD, Mao YQ, Zhu LJ, et al. Changes of regulatory T cells and FoxP3 gene expression in the aging process and its relationship with lung tumors in humans and mice. Chin Med J Engl. 2012;125:2004–2011.
  • deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res. 2012;18(11):3022–3029. doi:10.1158/1078-0432.CCR-11-3216.
  • Fukushima Y, Minato N, Hattori M. The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm Regen. 2018;38:24.
  • Quinn KM, Fox A, Harland KL, et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T Cells. Cell Rep. 2018;23(12):3512–3524. doi:10.1016/j.celrep.2018.05.057.
  • Gong Z, Jia Q, Chen J, et al. Impaired cytolytic activity and loss of clonal neoantigens in elderly patients with lung adenocarcinoma. J Thorac Oncol. 2019;14(5):857–866. doi:10.1016/j.jtho.2019.01.024.
  • Sizova O, Kuriatnikov D, Liu Y, Su DM. Atrophied thymus, a tumor reservoir for harboring melanoma cells. Mol Cancer Res. 2018;16(11):1652–1664. doi:10.1158/1541-7786.MCR-18-0308.
  • Song Y, Yu R, Wang C, Chi F, Guo Z, Zhu X. Disruption of the thymic microenvironment is associated with thymic involution of transitional cell cancer. Urol Int. 2014;92(1):104–115. doi:10.1159/000353350.
  • Adkins B, Charyulu V, Sun QL, Lobo D, Lopez DM. Early block in maturation is associated with thymic involution in mammary tumor-bearing mice. J Immunol. 2000;164(11):5635–5640. doi:10.4049/jimmunol.164.11.5635.
  • Carrio R, Lopez DM. Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med. 2009;23(1):89–98.
  • Carrio R, Altman NH, Lopez DM. Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. Cancer Immunol Immunother. 2009;58(12):2059–2072. doi:10.1007/s00262-009-0714-7.
  • Susana FM, Paula P, Slobodianik N. Dietary modulation of thymic enzymes. Endocr Metab Immune Disord Drug Targets. 2014;14(4):309–312. doi:10.2174/1871530314666140915125248.
  • Malpuech-Brugere C, Nowacki W, Gueux E, et al. Accelerated thymus involution in magnesium-deficient rats is related to enhanced apoptosis and sensitivity to oxidative stress. Br J Nutr. 1999;81(5):405–411. doi:10.1017/S0007114599000690.
  • Nodera M, Yanagisawa H, Wada O. Increased apoptosis in a variety of tissues of zinc-deficient rats. Life Sci. 2001;69(14):1639–1649. doi:10.1016/S0024-3205(01)01252-8.
  • Dardenne M, Boukaiba N, Gagnerault M-C, et al. Restoration of the Thymus in Aging Mice by in Vivo Zinc Supplementation. Clin Immunol Immunopathol. 1993;66(2):127–135. doi:10.1006/clin.1993.1016.
  • Fernandes G, Nair M, Onoe K, Tanaka T, Floyd R, Good RA. Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. Proc Natl Acad Sci U S A. 1979;76(1):457–461. doi:10.1073/pnas.76.1.457.
  • Wu D, Lewis ED, Pae M, Meydani SN. Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol. 2018;9:3160–3160. doi:10.3389/fimmu.2018.03160.
  • Hu C, Zhang K, Jiang F, Wang H, Shao Q. Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy. Clin Epigenetics. 2021;13(1):210. doi:10.1186/s13148-021-01197-0.
  • Zhang W, Li J, Suzuki K, et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348(6239):1160–1163. doi:10.1126/science.aaa1356.
  • Keenan CR, Iannarella N, Naselli G, et al. Extreme disruption of heterochromatin is required for accelerated hematopoietic aging. Blood. 2020;135(23):2049–2058. doi:10.1182/blood.2019002990.
  • Ortman CL, Dittmar KA, Witte PL, Le PT. Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol. 2002;14(7):813–822. doi:10.1093/intimm/dxf042.
  • Sidler C, Woycicki R, Li D, Wang B, Kovalchuk I, Kovalchuk O. A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts. Aging (Albany NY). 2014;6(7):545–563. doi:10.18632/aging.100678.
  • García-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet. 2004;36(1):94–99. doi:10.1038/ng1278.
  • Uhlírová R, Horáková AH, Galiová G, et al. SUV39h-and A-type lamin-dependent telomere nuclear rearrangement. J Cell Biochem. 2010;109(5):915–926.
  • Teghanemt A, Pulipati P, Day K, et al. Epigenetic Programming during thymic development sets the stage for optimal function in effector T cells via DNA demethylation. bioRxiv 2021.
  • Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol. 2010;11(6):512–519. doi:10.1038/ni.1874.
  • Träger U, Sierro S, Djordjevic G, et al. The immune response to melanoma is limited by thymic selection of self-antigens. PLoS One. 2012;7(4):e35005. doi:10.1371/journal.pone.0035005.
  • Bakhru P, Zhu ML, Wang HH, et al. Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity. JCI Insight. 2017;2(18):e93265 doi:10.1172/jci.insight.93265.
  • Ahern E, Harjunpää H, Barkauskas D, et al. Co-administration of RANKL and CTLA4 antibodies enhances lymphocyte-mediated antitumor immunity in mice. Clin Cancer Res. 2017;23(19):5789–5801. doi:10.1158/1078-0432.CCR-17-0606.
  • Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. doi:10.1056/NEJMoa0809493.
  • Lopes N, Vachon H, Marie J, Irla M. Administration of RANKL boosts thymic regeneration upon bone marrow transplantation. EMBO Mol Med. 2017;9(6):835–851. doi:10.15252/emmm.201607176.
  • Lo Iacono N, Blair HC, Poliani PL, et al. Osteopetrosis rescue upon RANKL administration to Rankl(-/-) mice: a new therapy for human RANKL-dependent ARO. J Bone Miner Res. 2012;27(12):2501–2510. doi:10.1002/jbmr.1712.
  • Zorn AM, Wells JM. Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol. 2009;25:221–251. doi:10.1146/annurev.cellbio.042308.113344.
  • Bredenkamp N, Ulyanchenko S, O’Neill KE, Manley NR, Vaidya HJ, Blackburn CC. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol. 2014;16(9):902–908. doi:10.1038/ncb3023.
  • Calderón L, Boehm T. Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell. 2012;149(1):159–172. doi:10.1016/j.cell.2012.01.049.
  • Bredenkamp N, Nowell CS, Blackburn CC. Regeneration of the aged thymus by a single transcription factor. Development. 2014;141(8):1627–1637. doi:10.1242/dev.103614.
  • Kim MJ, Miller CM, Shadrach JL, Wagers AJ, Serwold T. Young, proliferative thymic epithelial cells engraft and function in aging thymuses. J Immunol. 2015;194(10):4784–4795. doi:10.4049/jimmunol.1403158.
  • Pan B, Liu J, Zhang Y, et al. Acute ablation of DP thymocytes induces up-regulation of IL-22 and Foxn1 in TECs. Clin Immunol. 2014;150(1):101–108. doi:10.1016/j.clim.2013.11.002.
  • Rossi S, Blazar BR, Farrell CL, et al. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood. 2002;100(2):682–691. doi:10.1182/blood.v100.2.682.
  • Min D, Taylor PA, Panoskaltsis-Mortari A, et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood. 2002;99(12):4592–4600. doi:10.1182/blood.v99.12.4592.
  • Alpdogan O, Hubbard VM, Smith OM, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood. 2006;107(6):2453–2460. doi:10.1182/blood-2005-07-2831.
  • Coles AJ, Azzopardi L, Kousin-Ezewu O, et al. Keratinocyte growth factor impairs human thymic recovery from lymphopenia. JCI Insight. 2019;4(12):e125377. doi:10.1172/jci.insight.125377.
  • Goonewardene SS, Persad R, Young A, Makar A. Re: impact of androgen deprivation therapy on mental and emotional well-being in men with prostate cancer: analysis from the CaPSURE™ registry: K. C. Cary, N. Singla, J. E. Cowan, P. R. Carroll and M. R. Cooperberg. J Urol 2014; 191: 964-970. J Urol. 2014;192(6):1889–1890. doi:10.1016/j.juro.2014.06.091.
  • Dragin N, Bismuth J, Cizeron-Clairac G, et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 2016;126(4):1525–1537. doi:10.1172/JCI81894.
  • Brown MA, Su MA. An inconvenient variable: sex hormones and their impact on T cell responses. J Immunol. 2019;202(7):1927–1933. doi:10.4049/jimmunol.1801403.
  • Bakhru P, Su MA. Estrogen turns down “the AIRE”. J Clin Invest. 2016;126(4):1239–1241. doi:10.1172/JCI86800.
  • Kelly RM, Highfill SL, Panoskaltsis-Mortari A, et al. Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood. 2008;111(12):5734–5744. doi:10.1182/blood-2008-01-136531.
  • Taub DD, Murphy WJ, Longo DL. Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways. Curr Opin Pharmacol. 2010;10(4):408–424. doi:10.1016/j.coph.2010.04.015.
  • Mocchegiani E, Santarelli L, Muzzioli M, Fabris N. Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice. Int J Immunopharmacol. 1995;17(9):703–718. doi:10.1016/0192-0561(95)00059-B.
  • Wong CP, Song Y, Elias VD, Magnusson KR, Ho E. Zinc supplementation increases zinc status and thymopoiesis in aged mice. J Nutr. 2009;139(7):1393–1397. doi:10.3945/jn.109.106021.
  • Moretto MM, Hwang S, Chen K, Khan IA. Complex and multilayered role of IL-21 signaling during thymic development. J Immunol. 2019;203(5):1242–1251. doi:10.4049/jimmunol.1800743.
  • Pan B, Zhang F, Lu Z, et al. Donor T-cell-derived interleukin-22 promotes thymus regeneration and alleviates chronic graft-versus-host disease in murine allogeneic hematopoietic cell transplant. Int Immunopharmacol. 2019;67:194–201. doi:10.1016/j.intimp.2018.12.023.

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