TNF receptor-deficient mice reveal striking differences between several models of thymocyte negative selection.
Central tolerance depends upon Ag-mediated cell death in developing thymocytes. However, the mechanism of induced death is poorly understood. Among the known death-inducing proteins, TNF was previously found to be constitutively expressed in the thymus. The role of TNF in thymocyte negative selection was therefore investigated using TNF receptor (TNFR)-deficient mice containing a TCR transgene. TNFR-deficient mice displayed aberrant negative selection in two models: an in vitro system in which APC are cultured with thymocytes, and a popular in vivo system in which mice are treated with anti-CD3 Abs. In contrast, TNFR-deficient mice displayed normal thymocyte deletion in two Ag-induced in vivo models of negative selection. Current models of negative selection and the role of TNFR family members in this process are discussed in light of these results.
Page
D M
DM
Department of Biology and the Cancer Center, University of California-San Diego, La Jolla 92093-0687, USA. page@biomail.ucsd.edu
Roberts
E M
EM
Peschon
J J
JJ
Hedrick
S M
SM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D000941:Antigens; D017252:CD3 Complex / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D002478:Cells, Cultured; D017637:Clonal Deletion; D005260:Female; D005434:Flow Cytometry; D006182:H-Y Antigen / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D017730:Ki-1 Antigen / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency*; D013950:Thymus Gland / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000941:Antigens; D017252:CD3 Complex; D019013:CD40 Antigens; D006182:H-Y Antigen; D000949:Histocompatibility Antigens Class II; D017730:Ki-1 Antigen; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha