Differential Expression and Molecular Associations of Syk in Systemic Lupus Erythematosus T Cells

Abstract

Diminished expression of TCR ζ and reciprocal up-regulation and association of FcRγ with the TCR/CD3 complex is a hallmark of systemic lupus erythematosus (SLE) T cells. In this study we explored whether differential molecular associations of the spleen tyrosine kinase Syk that preferentially binds to FcRγ contribute to pathological amplification of signals downstream of this “rewired TCR” in SLE. We detected higher amounts of Syk expression and activity in SLE compared with normal T cells. Selective inhibition of the activity of Syk reduced the strength of TCR-induced calcium responses and slowed the rapid kinetics of actin polymerization exclusively in SLE T cells. Syk and ZAP-70 also associated differently with key molecules involved in cytoskeletal and calcium signaling in SLE T cells. Thus, while Vav-1 and LAT preferentially bound to Syk, phospholipase C-γ1 bound to both Syk and ZAP-70. Our results show that differential associations of Syk family kinases contribute to the enhanced TCR-induced signaling responses in SLE T cells. Thus, we propose molecular targeting of Syk as a measure to control abnormal T cell responses in SLE.

Induced Expression of FcγRIIIa (CD16a) on CD4+ T Cells Triggers Generation of IFN-γhigh Subset

“…SLE is a disease associated with the formation of DNA/RNA containing ICs and hyperactive T cells that also demonstrate activation of Syk (56). It is likely that ICs mediated IFN-␥ production in CD4 ϩ T-cells also require Syk activation (Fig.…”

Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

“…Furtherin SLE patients appears to be multifactorial. Biochemical characterization of the TCR signaling apparatus in T cells isolated from SLE patients indicates that changes in the assembly of the antigen receptor signal transduction machinery are mediated by the replacement of some signaling proteins (8,11). The consequence of protein replacement is an alteration of the biochemical signaling pattern downstream of antigen receptor cross-linking and a subsequent perturbation of gene expression programs.…”

Novel treatments for systemic lupus erythematosus

“…Higher amounts of Syk expression and activity were detected in T cells of SLE patients compared with normal T cells. Selective inhibition of the activity of Syk reversed aberrant T-cell signaling in SLE patients [Krishnan et al 2008]. R788, an orally bioavailable Syk inhibitor, delayed the development of renal disease and significantly prolonged survival of lupus-prone NZB/NZW mice [Bahjat et al 2008].…”