Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling

Alexandros P Grammatikos,Debjani Ghosh,Vasileios C Kyttaris,George C Tsokos,Amy Devlin,Stamatis-Nick Liossis

doi:10.1371/journal.pone.0074550

Abstract

Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.

Highlights

Following recognition of an antigen on the surface of a major histocompatibility complex (MHC) molecule, the T cell receptor (TCR) initiates a number of signaling cascades that determine cytokine production, cell survival, proliferation and differentiation
It is established that spleen tyrosine kinase (Syk) is increased in systemic lupus erythematosus (SLE) T cells it has not been previously shown whether increased Syk expression represents a primary or a secondary abnormality in these cells
SLE T cells display upon activation increased calcium flux, tyrosine phosphorylation and actin polymerization [14]

Summary

Introduction

Following recognition of an antigen on the surface of a major histocompatibility complex (MHC) molecule, the T cell receptor (TCR) initiates a number of signaling cascades that determine cytokine production, cell survival, proliferation and differentiation. The initial event, phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytosolic side of the TCR/CD3ζ chain complex, allows for Zap (ζ-chain associated protein kinase) to be recruited to CD3ζ. Zap becomes activated in this way and promotes the recruitment and phosphorylation of other adaptor molecules responsible of transmitting signals downstream. Instead of transmitting signals through TCR to CD3ζ and Zap, an alternative pathway comes into play involving FcRγ and spleen tyrosine kinase (Syk) [3,4]. As a result, following activation, SLE T cells exhibit higher intracytoplasmic calcium flux and cytosolic protein tyrosine phosphorylation [7,8]

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Conclusion