A model for antigen-specific T-cell anergy: displacement of CD4-p56(lck) signalosome from the lipid rafts by a soluble, dimeric peptide-MHC class II chimera.
Soluble, dimeric peptide-MHC chimeras were shown to induce Ag-specific T cell anergy in vitro and in vivo. In this study, we describe a mechanism by which a soluble, dimeric peptide MHC class II chimera (DEF) induces Ag-specific T cell anergy. The anergic cells showed a displacement of the CD4-p56(lck) signaling module from the GM1-rich plasma membrane microdomains (lipid rafts), and subsequently an increase in p59(fyn) kinase activity, a dominant expression of p21 inhibitory TCR zeta-chain, and a poor phosphorylation and recruitment of zeta-associated protein of 70 kDa kinase to the TCR's immunoreceptor tyrosine-based activation motifs. The Th1 and Th2 transcription was suppressed and the cells were arrested in the Th0 stage of differentiation. Recovery from DEF anergy occurred late and spontaneously at the expense of low thresholds for activation-induced cell death. In contrast to DEF, a combination of TCR and CD4 mAbs did not induce such alterations or anergy, indicating that the ligand-mediated topology of TCR and CD4 coengagement can differentially affect the T cell function. Our results argue for a model of anergy in which the defective partitioning of signaling molecules in lipid rafts is an early, negative signaling event in T cells. Physiological ligands like DEF chimeras may provide new tools for silencing the autoimmune processes, and may also help in deciphering new mechanisms of negative regulation in T cells.
Thomas
Sunil
S
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Kumar
Rajeev
R
Preda-Pais
Anca
A
Casares
Sofia
S
Brumeanu
Teodor-D
TD
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis / Q000378:metabolism*; D017635:Clonal Anergy / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D019281:Dimerization; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008894:Milk Proteins; D018448:Models, Immunological; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008894:Milk Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017027:Protein Tyrosine Phosphatases