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Expression in Systemic Lupus Erythematosus T Cells1
,
,,¶
* Department of Cellular Injury and
Department of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910;
Department of Medicine and
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
¶ Rheumatology Service, Walter Reed Army Medical Center, Washington, D.C. 20307;
|| Section of Rheumatology, Washington Hospital Center, Washington, D.C. 20010; and
# Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201
T cells isolated from patients with systemic lupus erythematosus (SLE) express low levels of CD3
-chain, a critical molecule involved in TCR-mediated signaling, but the involved mechanisms are not fully understood. In this study we examined caspase-3 as a candidate for cleaving CD3 in SLE T cells. We demonstrate that SLE T cells display increased expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3 and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3 with lipid rafts and simultaneously reversed the abnormal lipid raft preclustering, heightened TCR-induced calcium responses, and reduced the expression of FcR
-chain exclusively in SLE T cells. We conclude that caspase-3 inhibitors can normalize SLE T cell function by limiting the excessive digestion of CD3-chain and suggest that such molecules can be considered in the treatment of this disease.
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