TNF-dependent overexpression of CCL21 is an underlying cause of progressive lympoaccumulation in generalized lymphoproliferative disorder

Florian Wiede, Karen Vana, Lisa M. Sedger, Anja Lechner, Heinrich Körner*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The human condition autoimmune lymphoproliferative syndrome and the murine mutation generalized lymphoproliferative disorder (gld/gld) are both caused by mutations of Fas or Fas ligand and are characterized by severe splenomegaly and lymphadenopathy. in the mouse, the additional absence of TNF attenuates the gld/gld syndrome through an unknown mechanism. We hypothesized that this unexpected outcome was not mediated by increased apoptosis but changes of T cell localization. We demonstrated that the homeostatic chemokine CCL21 is strongly up-regulated in the spleen of C57BL/6 (B6).gld/gld and B6.gld-/-gld.TRAIL-/- mice. in contrast, a distinct consequence of TNF deficiency in B6.gld/gld mice was the substantially reduced splenic production of CCL21. An analysis of the cognate chemokine receptor CCR7 showed a complete, age-dependent down-regulation of this receptor on B6.gld/gld conventional peripheral T cells that are therefore unable to react to this chemokine. These results demonstrate a new role for the pro-inflammatory cytokine TNF and the TNF-regulated chemokine CCL21 in the complex etiology of the autoimmune syndrome in B6.gld/gld mice.

Original languageEnglish
Pages (from-to)351-357
Number of pages7
JournalEuropean Journal of Immunology
Volume37
Issue number2
DOIs
Publication statusPublished - Feb 2007

Keywords

  • Autoimmunity
  • Chemokine receptor
  • Knockout mice
  • Splenomegaly
  • T cells

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