We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Differential recognition and activation thresholds in human autoreactive GAD-specific T-cells.
- Authors
Mallone, Roberto; Kochik, Sharon A.; Laughlin, Elsa M.; Gersuk, Vivian H.; Reijonen, Helena; Kwok, William W.; Nepom, Gerald T.
- Abstract
The activation requirements of autoreactive CD4+ Tcells were investigated in GAD65-specific HLA-DR0401restricted 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)-γ1 phosphorylation and Ca2+ 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, [³H]-thymidine incorporation decreased at high TMr-GAD concentrations because of activationinduced 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.
- Subjects
T cells; LYMPHOCYTES; PEOPLE with diabetes; HLA histocompatibility antigens; BINDING sites; CELL membranes; MESSENGER RNA
- Publication
Diabetes, 2004, Vol 53, Issue 4, p971
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.4.971