Getting back at nature: Understanding thymic development and overcoming its atrophy

Current Opinion in Pharmacology

Volumn 10, Issue 4, 2010, Pages 425-433

  Heng, Tracy SP ^a   Chidgey, Ann P ^a   Boyd, Richard L ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOIMMUNE REGULATOR PROTEIN; BONE MORPHOGENETIC PROTEIN; CD40 LIGAND; CYCLOPHOSPHAMIDE; FLT3 LIGAND; GHRELIN; GROWTH HORMONE; INTERLEUKIN 7; KERATINOCYTE GROWTH FACTOR; PROTEIN TYROSINE KINASE; SEX HORMONE; SOMATOMEDIN C; STEM CELL FACTOR; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR RELA; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

AGING; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; CELL DIFFERENTIATION; DIABETES MELLITUS; DRUG HALF LIFE; GROWTH HORMONE DEFICIENCY; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOLOGICAL TOLERANCE; IMMUNOSTIMULATION; MICROENVIRONMENT; NONHUMAN; ORGANOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REJUVENATION; REVIEW; STEM CELL; T LYMPHOCYTE; THYMOCYTE; THYMUS; THYMUS ATROPHY;

AGING; ANIMALS; ANTINEOPLASTIC AGENTS; ATROPHY; EPITHELIAL CELLS; FIBROBLAST GROWTH FACTOR 7; FMS-LIKE TYROSINE KINASE 3; GONADAL STEROID HORMONES; GROWTH HORMONE; HUMANS; INSULIN-LIKE GROWTH FACTOR I; INTERLEUKIN-7; MEMBRANE PROTEINS; STEM CELLS; STROMAL CELLS; T-LYMPHOCYTES; THYMUS GLAND;

EID: 77955274421     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.coph.2010.04.006     Document Type: Review

References (71)

1. Gordon J., Wilson V.A., Blair N.F., Sheridan J., Farley A., Wilson L., Manley N.R., Blackburn C.C. Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol 2004, 5:546-553.
2. Gill J., Malin M., Hollander G.A., Boyd R. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 2002, 3:635-642.
3. Bennett A.R., Farley A., Blair N.F., Gordon J., Sharp L., Blackburn C.C. Identification and characterization of thymic epithelial progenitor cells. Immunity 2002, 16:803-814.
4. Gordon J., Bennett A.R., Blackburn C.C., Manley N.R. Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev 2001, 103:141-143.
5. Su D.M., Navarre S., Oh W.J., Condie B.G., Manley N.R. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol 2003, 4:1128-1135.
6. Chen L., Xiao S., Manley N.R. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 2009, 113:567-574.
7. Balciunaite G., Keller M.P., Balciunaite E., Piali L., Zuklys S., Mathieu Y.D., Gill J., Boyd R., Sussman D.J., Hollander G.A. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol 2002, 3:1102-1108.
8. Bleul C.C., Boehm T. BMP signaling is required for normal thymus development. J Immunol 2005, 175:5213-5221.
9. Rossi S.W., Chidgey A.P., Parnell S.M., Jenkinson W.E., Scott H.S., Boyd R.L., Jenkinson E.J., Anderson G. Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 2007, 37:2411-2418.
10. Rossi S.W., Jenkinson W.E., Anderson G., Jenkinson E.J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 2006, 441:988-991.
11. Bleul C.C., Corbeaux T., Reuter A., Fisch P., Monting J.S., Boehm T. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 2006, 441:992-996.
12. Gray D.H., Seach N., Ueno T., Milton M.K., Liston A., Lew A.M., Goodnow C.C., Boyd R.L. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 2006, 108:3777-3785.
13. Shakib S., Desanti G.E., Jenkinson W.E., Parnell S.M., Jenkinson E.J., Anderson G. Checkpoints in the development of thymic cortical epithelial cells. J Immunol 2009, 182:130-137.
14. Hozumi K., Mailhos C., Negishi N., Hirano K., Yahata T., Ando K., Zuklys S., Hollander G.A., Shima D.T., Habu S. Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 2008, 205:2507-2513.
15. Koch U., Fiorini E., Benedito R., Besseyrias V., Schuster-Gossler K., Pierres M., Manley N.R., Duarte A., Macdonald H.R., Radtke F. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 2008, 205:2515-2523.
16. Gommeaux J., Gregoire C., Nguessan P., Richelme M., Malissen M., Guerder S., Malissen B., Carrier A. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol 2009, 39:956-964.
17. Nitta T., Murata S., Sasaki K., Fujii H., Ripen A.M., Ishimaru N., Koyasu S., Tanaka K., Takahama Y. Thymoproteasome shapes immunocompetent repertoire of CD8(+) T cells. Immunity 2010, 39:29-40.
18. Derbinski J., Schulte A., Kyewski B., Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001, 2:1032-1039.
19. Anderson M.S., Venanzi E.S., Klein L., Chen Z., Berzins S.P., Turley S.J., von Boehmer H., Bronson R., Dierich A., Benoist C., et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395-1401.
20. Gray D., Abramson J., Benoist C., Mathis D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 2007, 204:2521-2528.
21. Rossi S.W., Kim M.Y., Leibbrandt A., Parnell S.M., Jenkinson W.E., Glanville S.H., McConnell F.M., Scott H.S., Penninger J.M., Jenkinson E.J., et al. RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 2007, 204:1267-1272.
22. Irla M., Hugues S., Gill J., Nitta T., Hikosaka Y., Williams I.R., Hubert F.X., Scott H.S., Takahama Y., Hollander G.A., et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 2008, 29:451-463.
23. Hikosaka Y., Nitta T., Ohigashi I., Yano K., Ishimaru N., Hayashi Y., Matsumoto M., Matsuo K., Penninger J.M., Takayanagi H., et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 2008, 29:438-450.
24. Akiyama T., Shimo Y., Yanai H., Qin J., Ohshima D., Maruyama Y., Asaumi Y., Kitazawa J., Takayanagi H., Penninger J.M., et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 2008, 29:423-437.
25. Venanzi E.S., Gray D.H., Benoist C., Mathis D. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol 2007, 179:5693-5700.
26. Seach N., Ueno T., Fletcher A.L., Lowen T., Mattesich M., Engwerda C.R., Scott H.S., Ware C.F., Chidgey A.P., Gray D.H., et al. The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J Immunol 2008, 180:5384-5392.
27. Fontenot J.D., Rasmussen J.P., Williams L.M., Dooley J.L., Farr A.G., Rudensky A.Y. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005, 22:329-341.
28. Liston A., Nutsch K.M., Farr A.G., Lund J.M., Rasmussen J.P., Koni P.A., Rudensky A.Y. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc Natl Acad Sci U S A 2008, 105:11903-11908.
29. Fletcher A.L., Seach N., Reiseger J.J., Lowen T.E., Hammett M.V., Scott H.S., Boyd R.L. Reduced thymic Aire expression and abnormal NF-kappa B2 signaling in a model of systemic autoimmunity. J Immunol 2009, 182:2690-2699.
30. Fletcher A.L., Lowen T.E., Sakkal S., Reiseger J.J., Hammett M.V., Seach N., Scott H.S., Boyd R.L., Chidgey A.P. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J Immunol 2009, 183:823-831.
31. Sakaguchi S., Sakaguchi N. Thymus and autoimmunity, transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice. J Exp Med 1988, 167:1479-1485.
32. Gray D.H., Tull D., Ueno T., Seach N., Classon B.J., Chidgey A., McConville M.J., Boyd R.L. A unique thymic fibroblast population revealed by the monoclonal antibody MTS-15. J Immunol 2007, 178:4956-4965.
33. Kenins L., Gill J.W., Boyd R.L., Hollander G.A., Wodnar-Filipowicz A. Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation. J Exp Med 2008, 205:523-531.
34. Sutherland J.S., Goldberg G.L., Hammett M.V., Uldrich A.P., Berzins S.P., Heng T.S., Blazar B.R., Millar J.L., Malin M.A., Chidgey A.P., et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005, 175:2741-2753.
35. Douek D.C., McFarland R.D., Keiser P.H., Gage E.A., Massey J.M., Haynes B.F., Polis M.A., Haase A.T., Feinberg M.B., Sullivan J.L., et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998, 396:690-695.
36. Kimmig S., Przybylski G.K., Schmidt C.A., Laurisch K., Mowes B., Radbruch A., Thiel A. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 2002, 195:789-794.
37. Haines C.J., Giffon T.D., Lu L.S., Lu X., Tessier-Lavigne M., Ross D.T., Lewis D.B. Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J Exp Med 2009, 206:275-285.
38. Dion M.L., Poulin J.F., Bordi R., Sylvestre M., Corsini R., Kettaf N., Dalloul A., Boulassel M.R., Debre P., Routy J.P., et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity 2004, 21:757-768.
39. Heng T.S., Goldberg G.L., Gray D.H., Sutherland J.S., Chidgey A.P., Boyd R.L. Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 2005, 175:2982-2993.
40. Goronzy J.J., Weyand C.M. T cell development and receptor diversity during aging. Curr Opin Immunol 2005, 17:468-475.
41. Messaoudi I., Lemaoult J., Guevara-Patino J.A., Metzner B.M., Nikolich-Zugich J. Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med 2004, 200:1347-1358.
42. Yager E.J., Ahmed M., Lanzer K., Randall T.D., Woodland D.L., Blackman M.A. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 2008, 205:711-723.
43. Waterstrat A., Van Zant G. Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol 2009, 21:408-413.
44. Mackall C.L., Punt J.A., Morgan P., Farr A.G., Gress R.E. Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution. Eur J Immunol 1998, 28:1886-1893.
45. Nobori S., Shimizu A., Okumi M., Samelson-Jones E., Griesemer A., Hirakata A., Sachs D.H., Yamada K. Thymic rejuvenation and the induction of tolerance by adult thymic grafts. Proc Natl Acad Sci U S A 2006, 103:19081-19086.
46. Hakim F.T., Memon S.A., Cepeda R., Jones E.C., Chow C.K., Kasten-Sportes C., Odom J., Vance B.A., Christensen B.L., Mackall C.L., et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005, 115:930-939.
47. Dudakov J.A., Goldberg G.L., Reiseger J.J., Chidgey A.P., Boyd R.L. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J Immunol 2009, 182:6247-6260.
48. Dudakov J.A., Goldberg G.L., Reiseger J.J., Vlahos K., Chidgey A.P., Boyd R.L. Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J Immunol 2009, 183:7084-7094.
49. Goldberg G.L., Sutherland J.S., Hammet M.V., Milton M.K., Heng T.S., Chidgey A.P., Boyd R.L. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 2005, 80:1604-1613.
50. Barnard A.L., Chidgey A.P., Bernard C.C., Boyd R.L. Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis. Blood 2009, 113:204-213.
51. Goldberg G.L., King C.G., Nejat R.A., Suh D.Y., Smith O.M., Bretz J.C., Samstein R.M., Dudakov J.A., Chidgey A.P., Chen-Kiang S., et al. Luteinizing hormone-releasing hormone enhances T cell recovery following allogeneic bone marrow transplantation. J Immunol 2009, 182:5846-5854.
52. Sutherland J.S., Spyroglou L., Muirhead J.L., Heng T.S., Prieto-Hinojosa A., Prince H.M., Chidgey A.P., Schwarer A.P., Boyd R.L. Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin Cancer Res 2008, 14:1138-1149.
53. Kumar R., Langer J.C., Snoeck H.W. Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution. Blood 2006, 107:1974-1979.
54. Hauri-Hohl M.M., Zuklys S., Keller M.P., Jeker L.T., Barthlott T., Moon A.M., Roes J., Hollander G.A. TGF-beta signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution. Blood 2008, 112:626-634.
55. Alves N.L., Richard-Le Goff O., Huntington N.D., Sousa A.P., Ribeiro V.S., Bordack A., Vives F.L., Peduto L., Chidgey A., Cumano A., et al. Characterization of the thymic IL-7 niche in vivo. Proc Natl Acad Sci U S A 2009, 106:1512-1517.
56. Sportes C., Hakim F.T., Memon S.A., Zhang H., Chua K.S., Brown M.R., Fleisher T.A., Krumlauf M.C., Babb R.R., Chow C.K., et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008, 205:1701-1714.
57. Wils E.J., Braakman E., Verjans G.M., Rombouts E.J., Broers A.E., Niesters H.G., Wagemaker G., Staal F.J., Lowenberg B., Spits H., et al. Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J Immunol 2007, 178:3551-3557.
58. Fry T.J., Sinha M., Milliron M., Chu Y.W., Kapoor V., Gress R.E., Thomas E., Mackall C.L. Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution. Blood 2004, 104:2794-2800.
59. Rossi S.W., Jeker L.T., Ueno T., Kuse S., Keller M.P., Zuklys S., Gudkov A.V., Takahama Y., Krenger W., Blazar B.R., et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 2007, 109:3803-3811.
60. Alpdogan O., Hubbard V.M., Smith O.M., Patel N., Lu S., Goldberg G.L., Gray D.H., Feinman J., Kochman A.A., Eng J.M., et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 2006, 107:2453-2460.
61. Min D., Panoskaltsis-Mortari A., Kuro O.M., Hollander G.A., Blazar B.R., Weinberg K.I. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 2007, 109:2529-2537.
62. Jenq R.R., King C.G., Volk C., Suh D., Smith O.M., Rao U.K., Yim N.L., Holland A.M., Lu S.X., Zakrzewski J.L., et al. Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation. Blood 2009, 113:1574-1580.
63. Kelly R.M., Highfill S.L., Panoskaltsis-Mortari A., Taylor P.A., Boyd R.L., Hollander G.A., Blazar B.R. 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, 111:5734-5744.
64. Goldberg G.L., Alpdogan O., Muriglan S.J., Hammett M.V., Milton M.K., Eng J.M., Hubbard V.M., Kochman A., Willis L.M., Greenberg A.S., et al. Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol 2007, 178:7473-7484.
65. Alpdogan O., Muriglan S.J., Kappel B.J., Doubrovina E., Schmaltz C., Schiro R., Eng J.M., Greenberg A.S., Willis L.M., Rotolo J.A., et al. Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation. Transplantation 2003, 75:1977-1983.
66. Mayack SR, Shadrach JL, Kim FS, Wagers AJ: Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 2010, 463:495-500.
67. Youm Y.H., Yang H., Sun Y., Smith R.G., Manley N.R., Vandanmagsar B., Dixit V.D. Deficient ghrelin receptor-mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J Biol Chem 2009, 284:7068-7077.
68. Dixit V.D., Yang H., Sun Y., Weeraratna A.T., Youm Y.H., Smith R.G., Taub D.D. Ghrelin promotes thymopoiesis during aging. J Clin Invest 2007, 117:2778-2790.
69. Napolitano L.A., Schmidt D., Gotway M.B., Ameli N., Filbert E.L., Ng M.M., Clor J.L., Epling L., Sinclair E., Baum P.D., et al. Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 2008, 118:1085-1098.
70. Morrhaye G., Kermani H., Legros J.J., Baron F., Beguin Y., Moutschen M., Cheynier R., Martens H.J., Geenen V. Impact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients. PLoS ONE 2009, 4:e5668.
71. Seach N, Mattesich M, Abberton K, Matsuda K, Tilkorn DJ, Rophael J, Boyd RL, Morrison WA: Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part C Methods 2009, in press.