Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation

Journal of Immunology

Volumn 194, Issue 12, 2015, Pages 5825-5837

  Coder, Brandon D ^a   Wang, Hongjun ^b   Ruan, Linhui ^c   Su, Dong Ming ^a  

^a UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER   (United States)

^b JILIN MEDICAL COLLEGE   (China)

^c WENZHOU MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOIMMUNE REGULATOR PROTEIN; INTERLEUKIN 6; TUMOR NECROSIS FACTOR ALPHA; FORKHEAD TRANSCRIPTION FACTOR; WHN PROTEIN;

AGED; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOREACTIVE T LYMPHOCYTE; CHRONIC INFLAMMATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; INFLAMMATORY INFILTRATE; LYMPHOCYTE CLONE; LYMPHOCYTIC INFILTRATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; THYMUS ATROPHY; AGE; ANIMAL; ANTIGEN MEDIATED CLONAL SELECTION; AUTOIMMUNITY; CHRONIC DISEASE; CYTOLOGY; DISEASE MODEL; GENE SILENCING; GENETICS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; IMMUNOPHENOTYPING; INFLAMMATION; KNOCKOUT MOUSE; LYMPHOCYTE ACTIVATION; METABOLISM; PHENOTYPE; T LYMPHOCYTE SUBPOPULATION; THYMOCYTE; THYMUS; TUMOR MICROENVIRONMENT;

AGE FACTORS; ANIMALS; AUTOIMMUNITY; CELLULAR MICROENVIRONMENT; CHRONIC DISEASE; CLONAL DELETION; CLONAL SELECTION, ANTIGEN-MEDIATED; DISEASE MODELS, ANIMAL; FORKHEAD TRANSCRIPTION FACTORS; GENE KNOCKDOWN TECHNIQUES; IMMUNOPHENOTYPING; INFLAMMATION; LYMPHOCYTE ACTIVATION; MICE; MICE, KNOCKOUT; PHENOTYPE; T-LYMPHOCYTE SUBSETS; THYMOCYTES; THYMUS GLAND;

EID: 84931418361     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1500082     Document Type: Article

References (69)

1. Franceschi, C., and J. Campisi. 2014. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69(Suppl. 1): S4-S9.
2. Howcroft, T. K., J. Campisi, G. B. Louis, M. T. Smith, B. Wise, T. Wyss-Coray, A. D. Augustine, J. E. McElhaney, R. Kohanski, and F. Sierra. 2013. The role of inflammation in age-related disease. Aging (Albany, N.Y. Online) 5: 84-93.
3. Huber, S. A., P. Sakkinen, D. Conze, N. Hardin, and R. Tracy. 1999. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 19: 2364-2367.
4. Martinez, T. N., X. Chen, S. Bandyopadhyay, A. H. Merrill, and M. G. Tansey. 2012. Ceramide sphingolipid signaling mediates tumor necrosis factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons. Mol. Neurodegener. 7: 45.
5. Grivennikov, S. I., and M. Karin. 2011. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann. Rheum. Dis. 70(Suppl. 1): i104-i108.
6. Varadhan, R., W. Yao, A. Matteini, B. A. Beamer, Q. L. Xue, H. Yang, B. Manwani, A. Reiner, N. Jenny, N. Parekh, et al. 2014. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 69: 165-173.
7. Freund, A., A. V. Orjalo, P. Y. Desprez, and J. Campisi. 2010. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16: 238-246.
8. Dall'Olio, F., V. Vanhooren, C. C. Chen, P. E. Slagboom, M. Wuhrer, and C. Franceschi. 2013. N-glycomic biomarkers of biological aging and longevity: a link with inflammaging. Ageing Res. Rev. 12: 685-698.
9. Brunner, S., D. Herndler-Brandstetter, B. Weinberger, and B. Grubeck-Loebenstein. 2011. Persistent viral infections and immune aging. Ageing Res. Rev. 10: 362-369.
10. Nikolich-Zugich, J. 2008. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8: 512-522.
11. Palmer, E. 2003. Negative selection - clearing out the bad apples from the T-cell repertoire. Nat. Rev. Immunol. 3: 383-391.
12. + natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212: 8-27.
13. Wirnsberger, G., M. Hinterberger, and L. Klein. 2011. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89: 45-53.
14. Starr, T. K., S. C. Jameson, and K. A. Hogquist. 2003. Positive and negative selection of T cells. Annu. Rev. Immunol. 21: 139-176.
15. Josefowicz, S. Z., L. F. Lu, and A. Y. Rudensky. 2012. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30: 531-564.
16. Hogquist, K. A., T. A. Baldwin, and S. C. Jameson. 2005. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5: 772-782.
17. Lio, C. W., and C. S. Hsieh. 2008. A two-step process for thymic regulatory T cell development. Immunity 28: 100-111.
18. Waterfield, M., I. S. Khan, J. T. Cortez, U. Fan, T. Metzger, A. Greer, K. Fasano, M. Martinez-Llordella, J. L. Pollack, D. J. Erle, et al. 2014. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15: 258-265.
19. Metzger, T. C., and M. S. Anderson. 2011. Control of central and peripheral tolerance by Aire. Immunol. Rev. 241: 89-103.
20. Anderson, M. S., and M. A. Su. 2011. Aire and T cell development. Curr. Opin. Immunol. 23: 198-206.
21. Malchow, S., D. S. Leventhal, S. Nishi, B. I. Fischer, L. Shen, G. P. Paner, A. S. Amit, C. Kang, J. E. Geddes, J. P. Allison, et al. 2013. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339: 1219-1224.
22. Perry, J. S., C. W. Lio, A. L. Kau, K. Nutsch, Z. Yang, J. I. Gordon, K. M. Murphy, and C. S. Hsieh. 2014. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41: 414-426.
23. Guo, J., M. Rahman, L. Cheng, S. Zhang, A. Tvinnereim, and D. M. Su. 2011. Morphogenesis and maintenance of the 3D thymic medulla and prevention of nude skin phenotype require FoxN1 in pre- and post-natal K14 epithelium. J. Mol. Med. 89: 263-277.
24. Sun, L., J. Guo, R. Brown, T. Amagai, Y. Zhao, and D. M. Su. 2010. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell 9: 347-357.
25. Gallegos, A. M., and M. J. Bevan. 2006. Central tolerance: good but imperfect. Immunol. Rev. 209: 290-296.
26. Fletcher, A. L., N. Seach, J. J. Reiseger, T. E. Lowen, M. V. Hammett, H. S. Scott, and R. L. Boyd. 2009. Reduced thymic Aire expression and abnormal NF-κB2 signaling in a model of systemic autoimmunity. J. Immunol. 182: 2690-2699.
27. Rucci, F., P. L. Poliani, S. Caraffi, T. Paganini, E. Fontana, S. Giliani, F. W. Alt, and L. D. Notarangelo. 2011. Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency. Front. Immunol. 2: 2.
28. Fontenot, J. D., J. L. Dooley, A. G. Farr, and A. Y. Rudensky. 2005. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202: 901-906.
29. + thymic epithelial cells. J. Immunol. 178: 829-837.
30. Cheng, L., J. Guo, L. Sun, J. Fu, P. F. Barnes, D. Metzger, P. Chambon, R. G. Oshima, T. Amagai, and D. M. Su. 2010. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J. Biol. Chem. 285: 5836-5847.
31. Zhu, X., J. Gui, J. Dohkan, L. Cheng, P. F. Barnes, and D. M. Su. 2007. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell 6: 663-672.
32. Moon, J. J., H. H. Chu, J. Hataye, A. J. Pagán, M. Pepper, J. B. McLachlan, T. Zell, and M. K. Jenkins. 2009. Tracking epitope-specific T cells. Nat. Protoc. 4: 565-581.
33. Burnley, P., M. Rahman, H. Wang, Z. Zhang, X. Sun, Q. Zhuge, and D. M. Su. 2013. Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging. Cell Death Dis. 4: e932.
34. Yu, W., H. Nagaoka, M. Jankovic, Z. Misulovin, H. Suh, A. Rolink, F. Melchers, E. Meffre, and M. C. Nussenzweig. 1999. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400: 682-687.
35. Boursalian, T. E., J. Golob, D. M. Soper, C. J. Cooper, and P. J. Fink. 2004. Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5: 418-425.
36. McCaughtry, T. M., M. S. Wilken, and K. A. Hogquist. 2007. Thymic emigration revisited. J. Exp. Med. 204: 2513-2520.
37. Baaten, B. J., R. Tinoco, A. T. Chen, and L. M. Bradley. 2012. Regulation of antigen-experienced T cells: lessons from the quintessential memory marker CD44. Front. Immunol. 3: 23.
38. + T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27: 203-213.
39. Anderson, G., B. C. Harman, K. J. Hare, and E. J. Jenkinson. 2000. Microenvironmental regulation of T cell development in the thymus. Semin. Immunol. 12: 457-464.
40. Taniguchi, R. T., J. J. DeVoss, J. J. Moon, J. Sidney, A. Sette, M. K. Jenkins, and M. S. Anderson. 2012. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc. Natl. Acad. Sci. USA 109: 7847-7852.
41. DeVoss, J., Y. Hou, K. Johannes, W. Lu, G. I. Liou, J. Rinn, H. Chang, R. R. Caspi, L. Fong, and M. S. Anderson. 2006. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203: 2727-2735.
42. Xia, J., H. Wang, J. Guo, Z. Zhang, B. Coder, and D. M. Su. 2012. Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection. Aging Dis. 3: 248-259.
43. Jung, D., and F. W. Alt. 2004. Unraveling V(D)J recombination; insights into gene regulation. Cell 116: 299-311.
44. + medullary thymic epithelial cells. Nat. Immunol. 8: 351-358.
45. Hubert, F. X., S. A. Kinkel, G. M. Davey, B. Phipson, S. N. Mueller, A. Liston, A. I. Proietto, P. Z. Cannon, S. Forehan, G. K. Smyth, et al. 2011. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118: 2462-2472.
46. Raynor, J., C. S. Lages, H. Shehata, D. A. Hildeman, and C. A. Chougnet. 2012. Homeostasis and function of regulatory T cells in aging. Curr. Opin. Immunol. 24: 482-487.
47. Lages, C. S., I. Suffia, P. A. Velilla, B. Huang, G. Warshaw, D. A. Hildeman, Y. Belkaid, and C. Chougnet. 2008. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J. Immunol. 181: 1835-1848.
48. Sun, L., V. J. Hurez, S. R. Thibodeaux, M. J. Kious, A. Liu, P. Lin, K. Murthy, S. Pandeswara, T. Shin, and T. J. Curiel. 2012. Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells. Aging Cell 11: 509-519.
49. Decman, V., B. J. Laidlaw, T. A. Doering, J. Leng, H. C. Ertl, D. R. Goldstein, and E. J. Wherry. 2012. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. J. Immunol. 188: 1933-1941.
50. Δ/Δ mutant mice. J. Immunol. 179: 8153-8163.
51. - regulatory T cells. J. Immunol. 176: 4748-4756.
52. Tsukamoto, H., K. Clise-Dwyer, G. E. Huston, D. K. Duso, A. L. Buck, L. L. Johnson, L. Haynes, and S. L. Swain. 2009. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc. Natl. Acad. Sci. USA 106: 18333-18338.
53. Tsukamoto, H., G. E. Huston, J. Dibble, D. K. Duso, and S. L. Swain. 2010. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185: 4535-4544.
54. Chougnet, C. A., P. Tripathi, C. S. Lages, J. Raynor, A. Sholl, P. Fink, D. R. Plas, and D. A. Hildeman. 2011. A major role for Bim in regulatory T cell homeostasis. J. Immunol. 186: 156-163.
55. De Martinis, M., C. Franceschi, D. Monti, and L. Ginaldi. 2005. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 579: 2035-2039.
56. Franceschi, C., M. Bonafè, S. Valensin, F. Olivieri, M. De Luca, E. Ottaviani, and G. De Benedictis. 2000. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908: 244-254.
57. Franceschi, C., M. Capri, D. Monti, S. Giunta, F. Olivieri, F. Sevini, M. P. Panourgia, L. Invidia, L. Celani, M. Scurti, et al. 2007. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128: 92-105.
58. Campisi, J. 2011. Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 21: 107-112.
59. Liston, A., D. H. Gray, S. Lesage, A. L. Fletcher, J. Wilson, K. E. Webster, H. S. Scott, R. L. Boyd, L. Peltonen, and C. C. Goodnow. 2004. Gene dosage - limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J. Exp. Med. 200: 1015-1026.
60. Anderson, M. S., E. S. Venanzi, Z. Chen, S. P. Berzins, C. Benoist, and D. Mathis. 2005. The cellular mechanism of Aire control of T cell tolerance. Immunity 23: 227-239.
61. + T cell tolerance. Nat. Immunol. 11: 512-519.
62. Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479: 232-236.
63. Ink4a prevents cancer and promotes aging in lymphocytes. Blood 117: 3257-3267.
64. Sutherland, J. S., G. L. Goldberg, M. V. Hammett, A. P. Uldrich, S. P. Berzins, T. S. Heng, B. R. Blazar, J. L. Millar, M. A. Malin, A. P. Chidgey, and R. L. Boyd. 2005. Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175: 2741-2753.
65. Yang, H., Y. H. Youm, and V. D. Dixit. 2009. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J. Immunol. 183: 3040-3052.
66. Howard, J. K., G. M. Lord, G. Matarese, S. Vendetti, M. A. Ghatei, M. A. Ritter, R. I. Lechler, and S. R. Bloom. 1999. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104: 1051-1059.
67. Dooley, J., and A. Liston. 2012. Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. Eur. J. Immunol. 42: 1073-1079.
68. Goronzy, J. J., and C. M. Weyand. 2003. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity-catalysts of autoimmunity and chronic inflammation. Arthritis Res. Ther. 5: 225-234.
69. Ortman, C. L., K. A. Dittmar, P. L. Witte, and P. T. Le. 2002. Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int. Immunol. 14: 813-822.