Differential recognition and activation thresholds in human autoreactive GAD-specific T-cells.
The activation requirements of autoreactive CD4(+) T-cells were investigated in GAD65-specific HLA-DR0401-restricted clones derived from a diabetic patient using major histocompatibility complex (MHC) class II tetramers (TMrs) as stimulating agents. Despite the fact that TMrs loaded with an immunodominant-altered GAD peptide (TMr-GAD) bound a limited number of T-cell receptors, they were capable of efficiently delivering activation signals. These signals ranged from the early steps of phospholipase C (PLC)-gamma(1) phosphorylation and Ca(2+) mobilization to more complex events, such as CD69 upregulation, cytokine mRNA transcription and secretion, and proliferation. All the effects triggered by TMr-GAD were dose dependent. On the contrary, [(3)H]-thymidine incorporation decreased at high TMr-GAD concentrations because of activation-induced cell death (AICD) after initial proliferation. Lower-avidity clones (as defined by TMr-GAD binding) were less sensitive to activation as well as less susceptible to AICD compared with higher-avidity clones. Induction of apoptosis is a potential immunomodulatory target for therapeutic applications of MHC class II multimers, but the relative resistance of low-avidity T-cells may limit its benefits.
Mallone
Roberto
R
Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, USA.
Kochik
Sharon A
SA
Laughlin
Elsa M
EM
Gersuk
Vivian H
VH
Reijonen
Helena
H
Kwok
William W
WW
Nepom
Gerald T
GT
D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood; D020013:Calcium Signaling / Q000276:immunology; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000276:immunology*; D007700:Kinetics; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
D001323:Autoantibodies; D006684:HLA-DR Antigens; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2