TNF-dependent overexpression of CCL21 is an underlying cause of progressive lymphoaccumulation in generalized lymphoproliferative disorder.
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.
Wiede
Florian
F
Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, Erlangen, Germany.
Vana
Karen
K
Sedger
Lisa M
LM
Lechner
Anja
A
Körner
Heinrich
H
D000818:Animals; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
C515478:CCL21 protein, human; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha