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p56lckexpression in 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.

Significant findings

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.


The functional consequences of the p56lck defect are of interest because (1) during intrathymic maturation, the preferential association of p56lck with TCR/CD3 is required for the appropriate adjustment of threshold responses to autoantigens; and (2) differentiation toward the Th2 lineage requires high levels of recruited p56lck kinase, and diabetes in a non-obese diabetic mouse model is associated with a relative reduction of the Th2/Th1 cell ratio. More experiments are required to prove the role of this defect in diabetes development. However, the description of a constitutive T cell signalling abnormality in a T cell mediated autoimmune disease will permit further insights into how tolerance is broken down in diabetes and other autoimmune diseases.


T cell activation, western blot, immunoprecipitation,


  1. Nervi S, Atlan-Gepner C, Kahn-Perles B, Lecine P, Vialettes B, Imbert J, Naquet P: Specific deficiency of p56lckexpression in T lymphocytes from type 1 diabetic patients. J Immunol . 2000, 165: 5874-5883.

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Fournel, S. p56lckexpression in type 1 diabetes. Arthritis Res Ther 3, 66868 (2000).

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