Induction of T cell anergy by high concentrations of immunodominant native peptide is accompanied by IL-10 production and a block in JNK activity.
The ability to induce anergy in antigen-specific T cells has potential therapeutic value for altering pathologic immune responses. This study was undertaken to further analyze changes in cytokine production and intracellular signaling during anergy induction using high concentrations of native peptide ligand of tetanus toxoid (TT)- and myelin basic protein (MBP)-specific human T cell lines. The TT-selected T cell line could be rendered unresponsive to its dominant epitope in a dose-dependent manner (IC50 = 0.03 microg/ml). The TT-selected line, as well as three T cell clones established from this line, continued to produce IFN-gamma and significantly increased IL-4 and IL-10 production when anergy was induced with high concentrations of the immunodominant epitope. JNK enzymatic activity was blocked in anergized T cells. The MBP-selected line could likewise be rendered unresponsive by incubation with supraoptimal concentrations of immunodominant peptide and anergy induction was accompanied by IL-10 release. Both T cell lines could be anergized by the autopresentation of native peptide since anergy was induced in cultures lacking fresh antigen-presenting cells. This study shows that the mitogen-activated protein kinase cascade is blocked when anergy is induced to high concentrations of soluble peptide.
Department of Veterans Affairs Medical Center, Portland, Oregon, 97201, USA.
Y K
YK
Chou
I
I
Robey
C N
CN
Woody
W
W
Li
H
H
Offner
A A
AA
Vandenbark
M P
MP
Davey
D000368:Aged; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D004676:Myelin Basic Protein / Q000276:immunology*; D011494:Protein Kinases / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000502:physiology
D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D004676:Myelin Basic Protein; D013745:Tetanus Toxoid; D018808:Transcription Factor AP-1; D016753:Interleukin-10; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases