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Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus

  1. Author:
    Liepinsh, D. J.
    Kruglov, A. A.
    Galimov, A. R.
    Shakhov, A. N.
    Shebzukhov, Y. V.
    Kuchmiy, A. A.
    Grivennikov, S. I.
    Tumanov, A. V.
    Drutskaya, M. S.
    Feigenbaum, L.
    Kuprash, D. V.
    Nedospasov, S. A.

  2. Author Address

    Liepinsh, Dmitry J.; Kruglov, Andrei A.; Galimov, Arthur R.; Kuchmiy, Anna A.; Grivennikov, Sergei I.; Tumanov, Alexei V.; Drutskaya, Marina S.; Kuprash, Dmitry V.; Nedospasov, Sergei A.] Russian Acad Sci, Lab Mol Immunol, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. [Liepinsh, Dmitry J.; Shakhov, Alexander N.; Shebzukhov, Yuriy V.; Grivennikov, Sergei I.; Nedospasov, Sergei A.] SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. [Liepinsh, Dmitry J.; Shakhov, Alexander N.; Shebzukhov, Yuriy V.; Grivennikov, Sergei I.; Nedospasov, Sergei A.] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Kruglov, Andrei A.; Galimov, Arthur R.; Shebzukhov, Yuriy V.; Nedospasov, Sergei A.] German Rheumatism Res Ctr DRFZ, Berlin, Germany. [Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Ctr Canc Res, Frederick, MD 21701 USA.
    1. Year: 2009
  2. Journal: European Journal of Immunology
    1. 39
    2. 10
    3. Pages: 2906-2915
  4. Type of Article: Article
  1. Abstract:

    TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines, using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LT beta R- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LT beta R and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.

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  2. DOI: 10.1002/eji.200839191
  3. PMID: 19735075

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