Anergy induction by dimeric TCR ligands.
T cells that recognize particular self Ags are thought to be important in the pathogenesis of autoimmune diseases. In multiple sclerosis, susceptibility is associated with HLA-DR2, which can present myelin-derived peptides to CD4(+) T cells. To generate molecules that target such T cells based on the specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion protein with a bound peptide from myelin basic protein (MBP). Soluble, dimeric DR2/MBP peptide complexes activated MBP-specific T cells in the absence of signals from costimulatory or adhesion molecules. This initial signaling through the TCR rendered the T cells unresponsive (anergic) to subsequent activation by peptide-pulsed APCs. Fluorescent labeling demonstrated that anergic T cells were initially viable, but became susceptible to late apoptosis due to insufficient production of cytokines. Dimerization of the TCR with bivalent MHC class II/peptide complexes therefore allows the induction of anergy in human CD4(+) T cells with a defined MHC/peptide specificity.
Appel
H
H
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Seth
N P
NP
Gauthier
L
L
Wucherpfennig
K W
KW
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D019281:Dimerization; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D015802:HLA-DR2 Antigen; D007074:Immunoglobulin G; D007376:Interleukin-2; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C107908:myelin basic protein 85-99