- Paper Report
- Open Access
p56lckexpression in type 1 diabetes
- Sylvie Fournel1
© Current Science Ltd 2000
- Published: 13 December 2000
- T lymphocyte
- TCR-CD3 transduction pathway
- type 1 diabetes
Type 1 diabetes is a T cell-mediated autoimmune disease leading to the destruction of pancreatic islet ? cells. This disease is associated with numerous immunological abnormalities. A characteristic abnormality is decreased proliferation and altered cytokine production by T lymphocytes when exposed to TCR/CD3 agonists in vitro. This phenotype can be reversed by addition of costimulatory signals (eg combination of CD2/CD28 antibodies or exogenous cytokines), suggesting a constitutive defect in the TCR/CD3 signal transduction pathway. In T lymphocytes, TCR/CD3 engagement induces CD3?-chain phosphorylation by p56lck or p59fyn tyrosine kinases. CD3?-chain phosphorylation allows the docking and the phosphorylation of ZAP-70 tyrosine kinase, which in turn phosphorylates neighboring proteins such as linker for activation of T cells (LAT). After recruitment of various adaptor proteins, key effector enzymes such as phospholipase C ? (PLC-?) are activated. The authors studied TCR/CD3 transduction pathway in isolated T lymphocytes.
The CD3?-chain was hypophosphorylated in 70% of the patients tested versus none of control subjects. By contrast, phosphorylation of ZAP-70 was unaffected. The patients with CD3?-chain hypophosphorylation had reduced expression of p56lck in resting lymphocytes. The authors did not observe a decrease of p59fyn, LAT, PLC-? or PI3kinase expression. In some patients, this defect was linked to low level of p56lckmRNA, and resulted in the failure to efficiently induce the expression of the CD69 early activation marker. The authors propose that T cell deficiency in human type 1 diabetes is due to the selective decreased expression of the p56lck tyrosine kinase.
T cell activation, western blot, immunoprecipitation,