Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review)

Fenggen Yan, Xiumei Mo, Junfeng Liu, Siqi Ye, Xing Zeng, Dacan Chen, Fenggen Yan, Xiumei Mo, Junfeng Liu, Siqi Ye, Xing Zeng, Dacan Chen

Abstract

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

Figures

Figure 1.
Figure 1.
T cell development in the thymus. CD, cluster of differentiation; CMJ, corticomedullary junction; cTEC, cortical thymic epithelial cell; DN, differentiation; DP, double positive; mTEC, medullary thymic epithelial cell; SP, single positive.
Figure 2.
Figure 2.
Molecular mechanisms underlying the generation of thymic regulatory T cells. Molecular signals downstream of the TCR are presented. AP, activator protein; APC, antigen-presenting cell; BCL, B cell lymphoma; BTLA, B and T lymphocyte attenuator; Ca, calcium; CARMA, CARD-containing MAGUK protein; CD, cluster of differentiation; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IKKβ, inhibitor of nuclear factor κB; ITIM, immunoreceptor tyrosine-based inhibition motif; MEK, mitogen-activated extracellular signal-regulated kinase; MHC, major histocompatibility complex; FoxO, forkhead box protein O; FOXP3, forkhead box protein 3; NFAT, nuclear factor of activated T; Grb, growth factor receptor-bound protein; LAT, linker for activation of T cells; LCK, lymphocyte-specific protein tyrosine kinase p56; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; mTOR, mechanistic target of rapamycin; NF, nuclear factor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PK, protein kinase; PL, phospholipase; PTP, protein-tyrosine phosphatase; Ras, rat sarcoma also known as p21; Raf, rapidly accelerated fibrosarcoma; SHP, SH2-containing protein tyrosine phosphatase; SOS, Son of Sevenless; STIM, stromal interaction molecule; TAK, transforming growth factor beta-activated kinase; ZAP70, ζ-associated protein of 70 kD.
Figure 3.
Figure 3.
Role of cytokines in T cell development. CD, cluster of differentiation; DN, double negative; DP, double positive; IL, interleukin; Treg, regulatory T cell.
Figure 4.
Figure 4.
Model of stress-induced thymic atrophy, and thymosuppressive and thymostimulatory mediators. AIDS, acquired immunodeficiency syndrome; Cyc, cyclophosphamide; Dex, dexamethasone; Dox, doxorubicin; HIV, human immunodeficiency virus; hGH, human growth hormone; IL, interleukin; KGF, keratinocyte growth factor; TGF-β, transforming growth factor-β; TSLP, thymic stromal lymphopoietin.

References

    1. Gordon J, Manley NR. Mechanisms of thymus organogenesis and morphogenesis. Development. 2011;138:3865–3878. doi: 10.1242/dev.059998.
    1. Blackburn CC, Manley NR. Developing a new paradigm for thymus organogenesis. Nat Rev Immunol. 2004;4:278–289. doi: 10.1038/nri1331.
    1. Skogberg G, Lundberg V, Berglund M, Gudmundsdottir J, Telemo E, Lindgren S, Ekwall O. Human thymic epithelial primary cells produce exosomes carrying tissue-restricted antigens. Immunol Cell Biol. 2015;93:727–734. doi: 10.1038/icb.2015.33.
    1. Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1:31–40. doi: 10.1038/35095500.
    1. Su M, Hu R, Jin J, Yan Y, Song Y, Sullivan R, Lai L. Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells. Sci Rep. 2015;5:9882. doi: 10.1038/srep09882.
    1. Fan Y, Tajima A, Goh SK, Geng X, Gualtierotti G, Grupillo M, Coppola A, Bertera S, Rudert WA, Banerjee I, et al. Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts. Mol Ther. 2015;23:1262–1277. doi: 10.1038/mt.2015.77.
    1. van Ewijk W, Wang B, Hollander G, Kawamoto H, Spanopoulou E, Itoi M, Amagai T, Jiang YF, Germeraad WT, Chen WF, Katsura Y. Thymic microenvironments, 3-D versus 2-D? Semin Immunol. 1999;11:57–64. doi: 10.1006/smim.1998.0158.
    1. Nishizuka Y, Sakakura T. Thymus and reproduction: Sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969;166:753–755. doi: 10.1126/science.166.3906.753.
    1. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: Mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–564. doi: 10.1146/annurev.immunol.25.022106.141623.
    1. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12:157–167.
    1. Wang YM, Ghali J, Zhang GY, Hu M, Wang Y, Sawyer A, Zhou JJ, Hapudeniya DA, Wang Y, Cao Q, et al. Development and function of Foxp3(+) regulatory T cells. Nephrology (Carlton) 2016;21:81–85. doi: 10.1111/nep.12652.
    1. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007;204:57–63. doi: 10.1084/jem.20061852.
    1. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–197. doi: 10.1038/ni1428.
    1. Rosalia RA, Štěpánek I, Polláková V, Šímová J, Bieblová J, Indrová M, Moravcová S, Přibylová H, Bontkes HJ, Bubeník J, et al. Administration of anti-CD25 mAb leads to impaired α-galactosylceramide-mediated induction of IFN-γ production in a murine model. Immunobiology. 2013;218:851–859. doi: 10.1016/j.imbio.2012.10.012.
    1. Wong J, Obst R, Correia-Neves M, Losyev G, Mathis D, Benoist C. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J Immunol. 2007;178:7032–7041. doi: 10.4049/jimmunol.178.11.7032.
    1. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity. 2006;25:249–259. doi: 10.1016/j.immuni.2006.05.016.
    1. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity. 2004;21:267–277. doi: 10.1016/j.immuni.2004.07.009.
    1. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001;2:816–822. doi: 10.1038/ni0901-816.
    1. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: What thymocytes see (and don't see) Nat Rev Immunol. 2014;14:377–391. doi: 10.1038/nri3667.
    1. Chapman NM, Chi H. mTOR links environmental signals to T cell fate decisions. Front Immunol. 2015;5:686. doi: 10.3389/fimmu.2014.00686.
    1. Akimzhanov AM, Boehning D. IP3R function in cells of the immune system. WIREs Membr Transp Signal. 2012;1:329–339. doi: 10.1002/wmts.27.
    1. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O'Connor E, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR; Proc Natl Acad Sci USA; 2008; pp. 7797–7802.
    1. Schwarz A, Schumacher M, Pfaff D, Schumacher K, Jarius S, Balint B, Wiendl H, Haas J, Wildemann B. Fine-tuning of regulatory T cell function: The role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis. J Immunol. 2013;190:4965–4970. doi: 10.4049/jimmunol.1203224.
    1. Lin J, Yang L, Silva HM, Trzeciak A, Choi Y, Schwab SR, Dustin ML, Lafaille JJ. Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus. Nat Commun. 2016;7:10562. doi: 10.1038/ncomms10562.
    1. Engel M, Sidwell T, Vasanthakumar A, Grigoriadis G, Banerjee A. Thymic regulatory T cell development: Role of signalling pathways and transcription factors. Clin Dev Immunol. 2013;2013:617595. doi: 10.1155/2013/617595.
    1. Ouyang W, Beckett O, Ma Q, Paik Jh, DePinho RA, Li MO. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol. 2010;11:618–627. doi: 10.1038/ni.1884.
    1. Kerdiles YM, Stone EL, Beisner DL, McGargill MA, Ch'en IL, Stockmann C, Katayama CD, Hedrick SM. Foxo transcription factors control regulatory T cell development and function. Immunity. 2010;33:890–904. doi: 10.1016/j.immuni.2010.12.002.
    1. Harada Y, Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. 2010;207:1381–1391. doi: 10.1084/jem.20100004.
    1. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35:109–122. doi: 10.1016/j.immuni.2011.03.029.
    1. Omenetti S, Pizarro TT. The Treg/Th17 axis: A dynamic balance regulated by the gut microbiome. Front Immunol. 2015;6:639. doi: 10.3389/fimmu.2015.00639.
    1. Nitta T, Suzuki H. Thymic stromal cell subsets for T cell development. Cell Mol Life Sci. 2016;73:1021–1037. doi: 10.1007/s00018-015-2107-8.
    1. Yarilin AA, Belyakov IM. Cytokines in the thymus: Production and biological effects. Curr Med Chem. 2004;11:447–464. doi: 10.2174/0929867043455972.
    1. Shitara S, Hara T, Liang B, Wagatsuma K, Zuklys S, Holländer GA, Nakase H, Chiba T, Tani-ichi S, Ikuta K. IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRγδ+ intraepithelial lymphocytes. J Immunol. 2013;190:6173–6179. doi: 10.4049/jimmunol.1202573.
    1. Tian T, Zhang J, Gao L, Qian XP, Chen WF. Heterogeneity within medullary-type TCRalphabeta(+)CD3(+)CD4(−)CD8(+) thymocytes in normal mouse thymus. Int Immunol. 2001;13:313–320. doi: 10.1093/intimm/13.3.313.
    1. Chemin K, Bohineust A, Dogniaux S, Tourret M, Guégan S, Miro F, Hivroz C. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol. 2012;189:2159–2168. doi: 10.4049/jimmunol.1200156.
    1. Coto JA, Hadden EM, Sauro M, Zorn N, Hadden JW. Interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C; Proc Natl Acad Sci USA; 1992; pp. 7752–7756.
    1. Dalloul A, Arock M, Fourcade C, Hatzfeld A, Bertho JM, Debré P, Mossalayi MD. Human thymic epithelial cells produce interleukin-3. Blood. 1991;77:69–74.
    1. Galy AH, Dinarello CA, Kupper TS, Kameda A, Hadden JW. Effects of cytokines on human thymic epithelial cells in culture. II. Recombinant IL 1 stimulates thymic epithelial cells to produce IL6 and GM-CSF. Cell Immunol. 1990;129:161–175. doi: 10.1016/0008-8749(90)90195-W.
    1. Savino W, Mendes-da-Cruz DA, Lepletier A, Dardenne M. Hormonal control of T-cell development in health and disease. Nat Rev Endocrinol. 2016;12:77–89.
    1. Savino W, Dardenne M. Neuroendocrine control of thymus physiology. Endocr Rev. 2000;21:412–443. doi: 10.1210/edrv.21.4.0402.
    1. Muegge K, Vila MP, Durum SK. Interleukin-7: A cofactor for V(D)J rearrangement of the T cell receptor beta gene. Science. 1993;261:93–95. doi: 10.1126/science.7686307.
    1. Bayer AL, Yu A, Malek TR. Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells. J Immunol. 2007;178:4062–4071. doi: 10.4049/jimmunol.178.7.4062.
    1. Varas A, Vicente A, Romo T, Zapata AG. Role of IL-2 in rat fetal thymocyte development. Int Immunol. 1997;9:1589–1599. doi: 10.1093/intimm/9.10.1589.
    1. Weist BM, Kurd N, Boussier J, Chan SW, Robey EA. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat Immunol. 2015;16:635–641. doi: 10.1038/ni.3171.
    1. Meilin A, Sharabi Y, Shoham J. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium-v. Proliferation regulating activities in supernatants of human thymic epithelial cell cultures. Int J Immunopharmacol. 1997;19:39–47. doi: 10.1016/S0192-0561(96)00042-2.
    1. Zlotnik A, Ransom J, Frank G, Fischer M, Howard M. Interleukin 4 is a growth factor for activated thymocytes: Possible role in T-cell ontogeny; Proc Natl Acad Sci USA; 1987; pp. 3856–3860.
    1. Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30:636–645. doi: 10.1016/j.immuni.2009.04.010.
    1. Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity. 2009;31:401–411. doi: 10.1016/j.immuni.2009.08.011.
    1. Mittal SK, Roche PA. Suppression of antigen presentation by IL-10. Curr Opin Immunol. 2015;34:22–27. doi: 10.1016/j.coi.2014.12.009.
    1. Patel DD, Whichard LP, Radcliff G, Denning SM, Haynes BF. Characterization of human thymic epithelial cell surface antigens: phenotypic similarity of thymic epithelial cells to epidermal keratinocytes. J Clin Immunol. 1995;15:80–92. doi: 10.1007/BF01541736.
    1. Meilin A, Shoham J, Schreiber L, Sharabi Y. The role of thymocytes in regulating thymic epithelial cell growth and function. Scand J Immunol. 1995;42:185–190. doi: 10.1111/j.1365-3083.1995.tb03644.x.
    1. Baseta JG, Stutman O. TNF regulates thymocyte production by apoptosis and proliferation of the triple negative (CD3-CD4-CD8-) subset. J Immunol. 2000;165:5621–5630. doi: 10.4049/jimmunol.165.10.5621.
    1. Zúñiga-Pflücker JC, Jiang D, Lenardo MJ. Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation. Science. 1995;268:1906–1909. doi: 10.1126/science.7541554.
    1. Arzt E, Kovalovsky D, Igaz LM, Costas M, Plazas P, Refojo D, Páez-Pereda M, Reul JM, Stalla G, Holsboer F. Functional cross-talk among cytokines, T-cell receptor, and glucocorticoid receptor transcriptional activity and action. Ann NY Acad Sci. 2000;917:672–677. doi: 10.1111/j.1749-6632.2000.tb05433.x.
    1. Cohen-Kaminsky S, Delattre RM, Devergne O, Rouet P, Gimond D, Berrih-Aknin S, Galanaud P. Synergistic induction of interleukin-6 production and gene expression in human thymic epithelial cells by LPS and cytokines. Cell Immunol. 1991;138:79–93. doi: 10.1016/0008-8749(91)90134-W.
    1. Wang J, Zhuo Y, Yin L, Wang H, Jiang Y, Liu X, Zhang M, Du F, Xia S, Shao Q. Doxycycline protects thymic epithelial cells from mitomycin C-mediated apoptosis in vitro via Trx2-NF-κB-Bcl-2/Bax axis. Cell Physiol Biochem. 2016;38:449–460. doi: 10.1159/000438642.
    1. Shanley DP, Aw D, Manley NR, Palmer DB. An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol. 2009;30:374–381. doi: 10.1016/j.it.2009.05.001.
    1. Dooley J, Liston A. Molecular control over thymic involution: From cytokines and microRNA to aging and adipose tissue. Eur J Immunol. 2012;42:1073–1079. doi: 10.1002/eji.201142305.
    1. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987;49:273–280. doi: 10.1016/0092-8674(87)90568-X.
    1. Xing Y, Hogquist KA. T-Cell tolerance: Central and peripheral. Cold Spring Harb Perspect Biol. 2012;4(pii):a006957.
    1. Roberts JL, Sharrow SO, Singer A. Clonal deletion and clonal anergy in the thymus induced by cellular elements with different radiation sensitivities. J Exp Med. 1990;171:935–940. doi: 10.1084/jem.171.3.935.
    1. Kisielow P, Bluthmann H, Staerz UD, Steinmetz M, von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988;333:742–746. doi: 10.1038/333742a0.
    1. Ramsdell F, Fowlkes B. Clonal deletion versus clonal anergy: The role of the thymus in inducing self tolerance. Science. 1990;248:1342–1348. doi: 10.1126/science.1972593.
    1. Nurieva R, Wang J, Sahoo A. T-cell tolerance in cancer. Immunotherapy. 2013;5:513–531. doi: 10.2217/imt.13.33.
    1. Xing Y, Hogquist KA. T-cell tolerance: Central and peripheral. Cold Spring Harb Perspect Biol. 2012;4(pii):a006957.
    1. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003;3:199–210. doi: 10.1038/nri1027.
    1. Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA, Lechler RI, Bloom SR. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest. 1999;104:1051–1059. doi: 10.1172/JCI6762.
    1. Wang SD, Huang KJ, Lin YS, Lei HY. Sepsis-induced apoptosis of the thymocytes in mice. J Immunol. 1994;152:5014–5021.
    1. Müller-Hermelink HK, Sale GE, Borisch B, Storb R. Pathology of the thymus after allogeneic bone marrow transplantation in man. A histologic immunohistochemical study of 36 patients. Am J Pathol. 1987;129:242–256.
    1. Gruver AL, Sempowski GD. Cytokines, leptin, and stress-induced thymic atrophy. J Leukoc Biol. 2008;84:915–923. doi: 10.1189/jlb.0108025.
    1. Boyd E. The weight of the thymus gland in health and disease. Am J Dis Child. 1932;43:1162–1214.
    1. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–156. doi: 10.1002/path.2104.
    1. Aw D, Silva AB, Palmer DB. Immunosenescence: Emerging challenges for an ageing population. Immunology. 2007;120:435–446. doi: 10.1111/j.1365-2567.2007.02555.x.
    1. Fülöp T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol. 2013;4:271. doi: 10.3389/fimmu.2013.00271.
    1. Gruver AL, Ventevogel MS, Sempowski GD. Leptin receptor is expressed in thymus medulla and leptin protects against thymic remodeling during endotoxemia-induced thymus involution. J Endocrinol. 2009;203:75–85. doi: 10.1677/JOE-09-0179.
    1. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol. 2000;18:529–560. doi: 10.1146/annurev.immunol.18.1.529.
    1. Billard MJ, Gruver AL, Sempowski GD. Acute endotoxin-induced thymic atrophy is characterized by intrathymic inflammatory and wound healing responses. PLoS One. 2011;6:e17940. doi: 10.1371/journal.pone.0017940.
    1. Hick RW, Gruver AL, Ventevogel MS, Haynes BF, Sempowski GD. Leptin selectively augments thymopoiesis in leptin deficiency and lipopolysaccharide-induced thymic atrophy. J Immunol. 2006;177:169–176. doi: 10.4049/jimmunol.177.1.169.
    1. Zhou YJ, Peng H, Chen Y, Liu YL. Alterations of thymic epithelial cells in lipopolysaccharide-induced neonatal thymus involution. Chin Med J (Engl) 2016;129:59–65. doi: 10.4103/0366-6999.172577.
    1. Ann V Griffith, Venables T, Shi J, Farr A, van Remmen H, Szweda L, Fallahi M, Rabinovitch P, Petrie HT. Metabolic damage and premature thymus aging caused by stromal catalase deficiency. Cell Rep. 2015;12:1071–1079. doi: 10.1016/j.celrep.2015.07.008.
    1. Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: Is it ever too old to become young again? Nat Rev Immunol. 2009;9:57–62. doi: 10.1038/nri2471.
    1. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol. 2008;43:718–728. doi: 10.1016/j.exger.2008.05.016.
    1. Min D, Panoskaltsis-Mortari A, Kuro-o M, Holländer GA, Blazar BR, Weinberg KI. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood. 2007;109:2529–2537. doi: 10.1182/blood-2006-08-043794.
    1. Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Holländer GA. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood. 2007;109:3803–3811. doi: 10.1182/blood-2006-10-049767.
    1. Hsu HC, Zhang HG, Li L, Yi N, Yang PA, Wu Q, Zhou J, Sun S, Xu X, Yang X, et al. Age-related thymic involution in C57BL/6J × DBA/2J recombinant-inbred mice maps to mouse chromosomes 9 and 10. Genes Immun. 2003;4:402–410. doi: 10.1038/sj.gene.6363982.
    1. Frawley R, White K, Jr, Brown R, Musgrove D, Walker N, Germolec D. Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive chemicals. Environ Health Perspect. 2010;119:371–376. doi: 10.1289/ehp.1002358.
    1. Boehm T, Swann JB. Thymus involution and regeneration: Two sides of the same coin? Nat Rev Immunol. 2013;13:831–838. doi: 10.1038/nri3534.
    1. Bluth MH, Kohlhoff S, Norowitz KB, Silverberg JI, Chice S, Nowakowski M, Durkin HG, Smith-Norowitz TA. Immune responses in autoimmune hepatitis: Effect of prednisone and azathioprine treatment: Case report. Int J Med Sci. 2009;6:177–183. doi: 10.7150/ijms.6.177.
    1. Marchetti MC, Marco BD, Santini MC, Bartoli A, Delfino DV, Riccardi C. Dexamethasone-induced thymocytes apoptosis requires glucocorticoid receptor nuclear translocation but not mitochondrial membrane potential transition. Toxicol Lett. 2003;139:175–180. doi: 10.1016/S0378-4274(02)00431-9.
    1. Gould KA, Shull JD, Gorski J. DES action in the thymus: Inhibition of cell proliferation and genetic variation. Mol Cell Endocrinol. 2000;170:31–39. doi: 10.1016/S0303-7207(00)00336-1.
    1. Fletcher AL, Lowen TE, Sakkal S, Reiseger JJ, Hammett MV, Seach N, Scott HS, Boyd RL, Chidgey AP. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J Immunol. 2009;183:823–831. doi: 10.4049/jimmunol.0900225.
    1. Camacho IA, Singh N, Hegde VL, Nagarkatti M, Nagarkatti PS. Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kappaB and expression of Fas ligand in thymic stromal cells and consequent apoptosis in T cells. J Immunol. 2005;175:90–103. doi: 10.4049/jimmunol.175.1.90.
    1. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, West ML, Smith OM, Holland AM, Tsai JJ, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science. 2012;336:91–95. doi: 10.1126/science.1218004.
    1. Larance M, Lamond AI. Multidimensional proteomics for cell biology. Nat Rev Mol Cell Biol. 2015;16:269–280. doi: 10.1038/nrm3970.
    1. Leung EL, Cao ZW, Jiang ZH, Zhou H, Liu L. Network-based drug discovery by integrating systems biology and computational technologies. Brief Bioinform. 2013;14:491–505. doi: 10.1093/bib/bbs043.
    1. Turiák L, Misják P, Szabó TG, Aradi B, Pálóczi K, Ozohanics O, Drahos L, Kittel A, Falus A, Buzás EI, Vékey K. Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice. J Proteomics. 2011;74:2025–2033. doi: 10.1016/j.jprot.2011.05.023.
    1. Billing AM, Revets D, Hoffmann C, Turner JD, Vernocchi S, Muller CP. Proteomic profiling of rapid non-genomic and concomitant genomic effects of acute restraint stress on rat thymocytes. J Proteomics. 2012;75:2064–2079. doi: 10.1016/j.jprot.2012.01.008.
    1. Schulze WX, Usadel B. Quantitation in mass-spectrometry-based proteomics. Annu Rev Plant Biol. 2010;61:491–516. doi: 10.1146/annurev-arplant-042809-112132.
    1. Matt P, Fu Z, Fu Q, Van Eyk JE. Biomarker discovery: Proteome fractionation and separation in biological samples. Physiol Genomics. 2008;33:12–17. doi: 10.1152/physiolgenomics.00282.2007.
    1. Sultana R, Di Domenico F, Tseng M, Cai J, Noel T, Chelvarajan RL, Pierce WD, Cini C, Bondada S, St Clair DK, Butterfield DA. Doxorubicin-induced thymus senescence. J Proteome Res. 2010;9:6232–6241. doi: 10.1021/pr100465m.
    1. Ma C, Yue QX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Guo DA. Proteomic analysis of possible target-related proteins of cyclophosphamide in mice thymus. Food Chem Toxicol. 2009;47:1841–1847. doi: 10.1016/j.fct.2009.04.041.
    1. Kawakami T, Nagata T, Muraguchi A, Nishimura T. Proteomic approach to apoptotic thymus maturation. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;787:223–229. doi: 10.1016/S1570-0232(02)00174-5.
    1. Tyanova S, Albrechtsen R, Kronqvist P, Cox J, Mann M, Geiger T. Proteomic maps of breast cancer subtypes. Nat Commun. 2016;7:10259. doi: 10.1038/ncomms10259.
    1. Chan PP, Wasinger VC, Leong RW. Current application of proteomics in biomarker discovery for inflammatory bowel disease. World J Gastrointest Pathophysiol. 2016;7:27–37. doi: 10.4291/wjgp.v7.i1.27.
    1. Peng F, Zhan X, Li MY, Fang F, Li G, Li C, Zhang PF, Chen Z. Proteomic and bioinformatics analyses of mouse liver microsomes. Int J Proteomics. 2012;2012:832569. doi: 10.1155/2012/832569.
    1. Goh WW, Lee YH, Chung M, Wong L. How advancement in biological network analysis methods empowers proteomics. Proteomics. 2012;12:550–563. doi: 10.1002/pmic.201100321.
    1. Miller JF. Immunological function of the thymus. Lancet. 1961;2:748–749. doi: 10.1016/S0140-6736(61)90693-6.
    1. Burns JC, Franco A. The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. Expert Rev Clin Immunol. 2015;11:819–825. doi: 10.1586/1744666X.2015.1044980.
    1. Shankar-Hari M, Spencer J, Sewell WA, Rowan KM, Singer M. Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective. Crit Care. 2012;16:206. doi: 10.1186/cc10597.
    1. Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune gamma-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol. 2001;21:193–199. doi: 10.1023/A:1011039216251.
    1. Chaudhry MS, Velardi E, Malard F, van den Brink MR. Immune reconstitution after allogeneic hematopoietic stem cell transplantation: Time to T Up the thymus. J Immunol. 2017;198:40–46. doi: 10.4049/jimmunol.1601100.
    1. Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013;54:683–687. doi: 10.3109/10428194.2012.728597.
    1. Ekins S, Gupta RR, Gifford E, Bunin BA, Waller CL. Chemical space: Missing pieces in cheminformatics. Pharm Res. 2010;27:2035–2039. doi: 10.1007/s11095-010-0229-0.
    1. Dobson CM. Chemical space and biology. Nature. 2004;432:824–828. doi: 10.1038/nature03192.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する