The Journal of Physiological Sciences

, Volume 62, Issue 3, pp 173–184 | Cite as

T cells affect thymic involution during puberty by inducing regression of the adrenal reticularis

  • Yoshihiro Kushida
  • Sayaka Kumagai
  • Ken Gotoh
  • Masato Fujii
  • Maki Touma
  • Masamichi Hosono
Original Paper

Abstract

The thymus involutes after puberty, although the mechanism by which this process occurs remains poorly understood. The profile of thymic involution, which is inversely correlated with an increase in peripheral T cells, may indicate that the accumulation of T cells in the periphery is related to thymic atrophy. In this study, it was shown that the prevention of T cell generation delayed the initiation of thymic involution. The activation of T cells increased the serum concentration of glucocorticoid (GC) and thymic involution, which was completely prevented by adrenalectomy. In the adrenals of growing mice, the activity of the zona fasciculata, which produces GC, increased and plateaued by the weaning period; however, the zona reticularis (ZR), which produces dehydroepiandrosterone (DHEA) that has anti-GC actions, started to decline just before puberty. Thymic atrophy was preceded by the infiltration of activated T cells into the ZR and by the loss of ZR cells. Thus, T cells are involved in thymic involution, a process which was retarded by DHEA administration, through an increase in GC activity due to ZR cell-killing.

Keywords

Thymic involution T cell-mediated stress GC/DHEA ratio Dynamics of adrenal cortex 

Notes

Acknowledgments

The authors would like to thank Dr. Katsuiku Hirokawa (Emeritus Professor of Tokyo Medical and Dental University), Institute for Health and Life Sciences, Tokyo, Japan, for useful discussions and a critical reading of the manuscript. Thanks are also due to Dr. Shigeyasu Tanaka, Faculty of Science, Shizuoka University, Shizuoka, Japan, for helpful comments and technical advice.

References

  1. 1.
    Walford RL (1962) Auto-immunity and aging. J Gerontol 17:281–285PubMedGoogle Scholar
  2. 2.
    Macieira-Coelho A (2003) The immune theory. In: Macieira-Coelho A (ed) Biology of aging. Progress in Molecular and Subcellular Biology: Cell Immortalization, vol 30. Springer, HeidelbergGoogle Scholar
  3. 3.
    Henson SM, Aspinall R (2003) Aging and the immune system. In: Aspinall R (ed) Aging of organs and system. Kluwer, DordrechtGoogle Scholar
  4. 4.
    Mitchell WA, Aspinall R (2007) Immunosenescence, thymic involution and autoimmunity. In: Pawelec G (ed) Immunosenescence. Springer, New YorkGoogle Scholar
  5. 5.
    Utsuyama M, Kasai M, Kurashima C, Hirokawa K (1991) Age influence on the thymic capacity to promote differentiation of T-cells: induction of different composition of T-cell subsets by aging thymus. Mech Ageing Dev 58:267–277PubMedCrossRefGoogle Scholar
  6. 6.
    Hartwig M, Steinmann G (1994) On a causal mechanism of chronic thymic involution in man. Mech Ageing Dev 75:151–156PubMedCrossRefGoogle Scholar
  7. 7.
    Ortman CL, Dittmar KA, Witte PL, Le PT (2002) Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol 14:813–822PubMedCrossRefGoogle Scholar
  8. 8.
    Akita S, Malkin J, Melmed S (1996) Disrupted murine leukemia inhibitory factor (LIF) gene attenuates adrenocorticotropic hormone (ACTH) secretion. Endocrinology 137:3140–3143PubMedCrossRefGoogle Scholar
  9. 9.
    Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 164:2180–2187PubMedGoogle Scholar
  10. 10.
    Fry TJ, Mackall CL (2002) Current concepts of thymic aging. Semin Immunopathol 24:7–22CrossRefGoogle Scholar
  11. 11.
    Hirokawa K, Utsuyama M, Kobayashi S (2001) Hypothalamic control of thymic function. Cell Mol Biol 47:97–102PubMedGoogle Scholar
  12. 12.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556PubMedCrossRefGoogle Scholar
  13. 13.
    Andres R, Tobin JD (1977) Endocrine system. In: Finch CE, Hayflick L (eds) Handbook of the biological aging. Van Nostrand Reinhold, New YorkGoogle Scholar
  14. 14.
    Nawata H, Higuchi K, Yanase T, Takayanagi R, Kato K, Ibayashi H (1985) Mechanism of dissociation of cortisol and adrenal androgen secretion after removal of adrenocortical adenoma in patients with Cushing’s syndrome. Endocrinol Jpn 32:691–700PubMedCrossRefGoogle Scholar
  15. 15.
    Van Eekelen JA, Rots NY, Sutanto W, de Kloet ER (1992) The effect of aging on stress responsiveness and central corticosteroid receptors in the brown Norway rat. Neurobiol Aging 13:159–170PubMedCrossRefGoogle Scholar
  16. 16.
    Aspinall R (1997) Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development. J Immunol 158:3037–3045PubMedGoogle Scholar
  17. 17.
    Lau LL, Spain LM (2000) Altered aging-related thymic involution in T cell receptor transgenic, MHC-deficient, and CD4-deficient mice. Mech Ageing Dev 114:101–121PubMedCrossRefGoogle Scholar
  18. 18.
    Yoshida M, Gotoh K, Fujii M, Shimada H, Touma M, Hosono M (2007) Adrenal participation in thymocyte death by anti-CD3 antibodies in vivo. Microbiol Immunol 51:243–251PubMedCrossRefGoogle Scholar
  19. 19.
    Brewer JA, Kanagawa O, Sleckman BP, Muglia LJ (2002) Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo. J Immunol 169:1837–1843PubMedGoogle Scholar
  20. 20.
    May M, Holmes E, Rogers W, Poth M (1990) Protection from glucocorticoid induced thymic involution by dehydoroepiandrosterone. Life Sci 46:1627–1631PubMedCrossRefGoogle Scholar
  21. 21.
    Spencer NF, Norton SD, Harrison LL, Li GZ, Daynes RA (1996) Dysregulation of IL-10 production with aging: possible linkage to the age-associated decline in DHEA and its sulfated derivative. Exp Gerontol 31:393–408PubMedCrossRefGoogle Scholar
  22. 22.
    Blauer KL, Poth M, Rogers WM, Bernton EW (1991) Dehydroepiandrosterone antagonizes the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 129:3174–3179PubMedCrossRefGoogle Scholar
  23. 23.
    Kalimi M, Shafagoj Y, Loria R, Padgett D, Regelson W (1994) Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 131:99–104PubMedCrossRefGoogle Scholar
  24. 24.
    Kadish JL, Basch RS (1976) Hematopoietic thymocyte precursors. I. Assay and kinetics of the appearance of progeny. J Exp Med 143:1082–1099PubMedCrossRefGoogle Scholar
  25. 25.
    Eren R, Zharhary D, Abel L, Globerson A (1988) Age-related changes in the capacity of bone marrow cells to differentiate in thymic organ cultures. Cell Immunol 112:449–455PubMedCrossRefGoogle Scholar
  26. 26.
    Hirokawa K, Utsuyama M, Kasai M, Kurashima C, Ishijima S, Zeng YX (1994) Understanding the mechanism of the age-change of thymic function to promote T-cell differentiation. Immunol Lett 40:269–277PubMedCrossRefGoogle Scholar
  27. 27.
    Kelley KW, Brief S, Westly HJ, Novakofski J, Bechtel PJ, Simon J, Walker EB (1986) GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci USA 83:5663–5667PubMedCrossRefGoogle Scholar
  28. 28.
    Besedovsky H, Sorkin E (1977) Network of immune–neuroendocrine interactions. Clin Exp Immunol 27:1–12PubMedGoogle Scholar
  29. 29.
    Besedovsky H, Del Rey A, Sorkin E, Dinarello CA (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233:652–654PubMedCrossRefGoogle Scholar
  30. 30.
    Laccorazza HD, Patiño JAG, Weksler ME, Radu D, Nikolić-Žugić J (1999) Failure of rearranged TCR transgenes to prevent age-associated thymic involution. J Immunol 163:4262–4268Google Scholar
  31. 31.
    Touma M, Mori KJ, Hosono M (2000) Failure to remove autoreactive Vβ6+ T cells in Mls-1a newborn mice attributed to the delayed development of B cells in the thymus. Immunology 100:424–431PubMedCrossRefGoogle Scholar
  32. 32.
    Endoh A, Kristiansen SB, Casson PR, Buster JE, Hornsby PJ (1996) The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 81:3558–3565PubMedCrossRefGoogle Scholar
  33. 33.
    Rook GAW, Hernandez-Pando R, Lightman SL (1994) Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance. Immunol Today 15:301–303PubMedCrossRefGoogle Scholar
  34. 34.
    Jenkinson EJ, Owen JJ, Aspinall R (1980) Lymphocyte differentiation and major histocompatibility complex antigen expression in the embryonic thymus. Nature 284:177–179PubMedCrossRefGoogle Scholar
  35. 35.
    Rouse RV (1985) Is Ia antigen expression by thymic epithelial cells constitutive? In: Klaus GGB (ed) Microenvironment in the lymphoid system. Advances in. Experimental Medicine and Biology, vol 186. Plenum, New YorkGoogle Scholar
  36. 36.
    Marx C, Bornstein SR, Wolkersdörfer GW, Peter M, Sippell WG, Scherbaum WA (1997) Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex. J Clin Endocrinol Metab 82:3136–3140PubMedCrossRefGoogle Scholar
  37. 37.
    Wolkersdörfer GW, Lohmann T, Marx C, Schröder S, Pfeiffer R, Stahl HD, Scherbaum WA, Chrousos GP, Bornstein SR (1999) Lymphocytes stimulate dehydroepiandrosterone production through direct cellular contact with adrenal zona reticularis cells: a novel mechanism of immune-endocrine interaction. J Clin Endocrinol Metab 84:4220–4227PubMedCrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer 2012

Authors and Affiliations

  • Yoshihiro Kushida
    • 1
  • Sayaka Kumagai
    • 1
  • Ken Gotoh
    • 1
  • Masato Fujii
    • 1
  • Maki Touma
    • 1
  • Masamichi Hosono
    • 1
  1. 1.Laboratory of Immunobiology, Department of Life Science, Graduate School of Science and TechnologyNiigata UniversityNiigataJapan

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