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

Eur J Immunol. 2009 Oct;39(10):2906-15. doi: 10.1002/eji.200839191.


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-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Atrophy / genetics*
  • Atrophy / pathology
  • Bone Marrow Transplantation
  • Cell Count
  • Cell Proliferation
  • Epithelial Cells / pathology
  • Gene Dosage / genetics
  • Gene Expression / genetics*
  • Humans
  • Keratin-8 / metabolism
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin-alpha / genetics*
  • Lymphotoxin-alpha / metabolism
  • Lymphotoxin-beta / genetics*
  • Lymphotoxin-beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Stem Cells / pathology
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes / pathology
  • Thymus Gland / metabolism
  • Thymus Gland / pathology*
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism


  • Keratin-8
  • Krt8 protein, mouse
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha