Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis.
The recently described tumor necrosis factor (TNF) family member LIGHT (herpes virus entry mediator [HVEM]-L/TNFSF14), a ligand for the lymphotoxin (LT)beta 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(-/-)LTbeta(-/-) animals contain mesenteric lymph nodes as compared with LTbeta(-/-) mice, whereas the splenic microarchitecture of LIGHT(-/-)LTbeta(-/-) and LTbeta(-/-) mice shows a comparable state of disruption. This suggests the existance of an additional undiscovered ligand for the LTbeta receptor (LTbetaR) or a weak LTalpha(3)-LTbetaR 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 LTbeta in lymphoid organogenesis and indicates important costimulatory functions for LIGHT in T cell activation.
Scheu
Stefanie
S
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Germany.
Alferink
Judith
J
Pötzel
Tobias
T
Barchet
Winfried
W
Kalinke
Ulrich
U
Pfeffer
Klaus
K
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D017931:DNA Primers; D006085:Graft Survival; D008198:Lymph Nodes / Q000378:metabolism*; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D016038:Skin Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha