Activation signal transduction by beta1 integrin in T cells from patients with systemic lupus erythematosus

Nakayamada S, Saito K, Nakano K, Tanaka Y
Source: Arthritis Rheum
Publication Date: (2007)
Issue: 56(5): 1559-1568
Research Area:
Immunotherapy / Hematology
Cells used in publication:
T cell, human peripheral blood unstim.
Species: human
Tissue Origin: blood
T cell, human stim.
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
OBJECTIVE: Beta 1 integrin is a representative adhesion molecule for cell-cell and cell-extracellular matrix interactions, and it provides costimulatory signals to T cells. However, the relevance of beta1 integrin to T cell activation in systemic lupus erythematosus (SLE) remains unclear. We undertook this study to perform a quantitative and functional analysis of beta1 integrin-mediated signaling to T cells in patients with SLE. METHODS: Expression of cell surface molecules was assessed by flow cytometric analysis. Engagement of beta1 integrins was performed by crosslinking using a specific monoclonal antibody. To assess tyrosine kinases in beta1 integrin-mediated signaling, the cells were transfected with a wild-type (WT) focal adhesion kinase (FAK), a dominant-negative truncation of the FAK, or a WT PTEN expression plasmid via nucleofection. RESULTS: Beta 1 integrin expression was significantly up-regulated on peripheral blood T cells from patients with active SLE, particularly those with the complication of World Health Organization class IV nephritis, whereas CD28 was significantly decreased in patients with active SLE compared with normal individuals. Beta 1 integrin expression closely correlated with serum hypocomplementemia. Engagement of beta1 integrin on T cells from patients with active SLE, but not on those from normal individuals, induced cell proliferation as well as CD40L expression on T cells. Up-regulation of CD40L expression and T cell proliferation, induced by beta1 integrin stimulation, were completely inhibited by transfection of the dominant-negative truncations of FAK or WT PTEN. CONCLUSION: These results suggest that engagement of beta1 integrins on SLE T cells could induce FAK-mediated signaling and subsequent CD40L expression and proliferation. Thus, the beta1 integrin signaling cascade might serve to enhance autoreactive T cell activation.