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Originally published online as doi:10.1189/jlb.0107018 on October 23, 2008

Published online before print October 23, 2008
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(Journal of Leukocyte Biology. 2009;85:108-116.)
© 2009 by Society for Leukocyte Biology

Age-dependent, polyclonal hyperactivation of T cells is reduced in TNF-negative gld/gld mice

Florian Wiede*,{dagger},1, Alicia Roomberg*,1, Erika Cretney{ddagger}, Anja Lechner§, Phillip Fromm*, Leia Wren*, Mark J. Smyth|| and Heinrich Körner*,2

* Comparative Genomics Centre, James Cook University, Townsville, Australia;
{dagger} Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia;
{ddagger} The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;
§ Lehrstuhl für Immunologie, Universitätsklinikum Regensburg, Regensburg, Germany; and
|| Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

2 Correspondence: Comparative Genomics Centre, School of Veterinary and Biomedical Science/School of Pharmacy and Molecular Sciences, Molecular Sciences Bldg. 21, James Cook University, Townsville, Qld 4811, Australia. E-mail: heinrich.korner{at}jcu.edu.au

The generalized lymphoproliferative disorder (gld) mouse strain is characterized by severe splenomegaly/lymphadenopathy, the production of autoimmune antibodies, and the appearance of CD4/CD8-negative T cells. An additional TNF deficiency of gld/gld mice attenuates the course of the disorder through a yet-unknown mechanism. In this study, we could demonstrate that the reduced splenomegaly and lymphadenopathy in B6.gld/gld.TNF–/– mice were correlated with a decreased peripheral T cell proliferation rate and a delayed polyclonal activation. A comparative analysis of naïve T cells and memory/effector T cells showed an age-dependent difference in the T cell activation pattern in the spleen of B6.gld/gld and B6.gld/gld.TNF–/– mice. T cells from B6.gld/gld.TNF–/– spleens and lymph nodes showed significantly higher levels of CCR7 and CD62 ligand on their surface compared with B6.gld/gld mice when mice of the same age were compared. Additionally, we found an increased titer of the Th1 cytokine IFN-{gamma} in the serum of B6.gld/gld mice, whereas the concentration of IFN-{gamma} was markedly reduced in the serum of B6.gld/gld.TNF–/– mice. These findings support the hypothesis that increased T cell activation and proliferation in the presence of TNF contribute to the exacerbation of the gld syndrome.

Key Words: autoimmunity • knockout mice • tumor necrosis factor • Fas ligand