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

Dmitry J. Liepinsh, Andrei A. Kruglov, Arthur R. Galimov, Alexander N. Shakhov, Yuriy V. Shebzukhov, Anna A. Kuchmiy, Sergei I. Grivennikov, Alexei V. Tumanov, Marina S. Drutskaya, Lionel Feigenbaum, Dmitry V. Kuprash, Sergei A. Nedospasov

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

TNF, lymphotoxin (LT)-α, LT-β 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-, LTbR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-α/LT-β to LTβR and TNF/LT-α to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.

Original languageEnglish (US)
Pages (from-to)2906-2915
Number of pages10
JournalEuropean Journal of Immunology
Volume39
Issue number10
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Keywords

  • Cytokine receptors
  • Cytokines
  • T cells
  • Thymus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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