The Journal of Experimental Medicine
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Published online 10 June 2002 doi:10.1084/jem.20020215
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© Rockefeller University Press, 0022-1007/2002/6/1613/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 12, June 17, 2002 1613-1624

Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin ß in Mesenteric Lymph Node Genesis

Stefanie Scheu1, Judith Alferink1, Tobias Pötzel1, Winfried Barchet2, Ulrich Kalinke2 and Klaus Pfeffer1

1 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich, Germany
2 Department of Immunology, Paul-Ehrlich-Institute, D-63225 Langen, Germany

Address correspondence to Klaus Pfeffer, Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich Trogerstr 9, D-81675 Munich, Germany. Phone: 49-89-4140-4132; Fax: 49-89-4140-4139; E-mail: klaus.pfeffer{at}lrz.tu-muenchen.de

The recently described tumor necrosis factor (TNF) family member LIGHT (herpes virus entry mediator [HVEM]-L/TNFSF14), a ligand for the lymphotoxin (LT)ß receptor, HVEM, and DcR3, was inactivated in the mouse. In contrast to mice deficient in any other member of the LT core family, LIGHT-/- mice develop intact lymphoid organs. Interestingly, a lower percentage of LIGHT-/-LTß-/- animals contain mesenteric lymph nodes as compared with LTß-/- mice, whereas the splenic microarchitecture of LIGHT-/-LTß-/- and LTß-/- mice shows a comparable state of disruption. This suggests the existance of an additional undiscovered ligand for the LTß receptor (LTßR) or a weak LT{alpha}3–LTßR interaction in vivo involved in the formation of secondary lymphoid organs. LIGHT acts synergistically with CD28 in skin allograft rejection in vivo. The underlying mechanism was identified in in vitro allogeneic MLR studies, showing a reduced cytotoxic T lymphocyte activity and cytokine production. Detailed analyses revealed that proliferative responses specifically of CD8+ T cells are impaired and interleukin 2 secretion of CD4+ T cells is defective in the absence of LIGHT. Furthermore, a reduced 3[H]-thymidine incorporation after T cell receptor stimulation was observed. This for the first time provides in vivo evidence for a cooperative role for LIGHT and LTß in lymphoid organogenesis and indicates important costimulatory functions for LIGHT in T cell activation.

Key Words: TNF • lymphotoxin • HVEM • lymphoid organogenesis • transplantation


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