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Differential Expression and Molecular Associations of Syk in Systemic Lupus Erythematosus T Cells¹

Sandeep Krishnan,^2* Yuang-Taung Juang,² Bhabadeb Chowdhury,^2* Abigail Magilavy, Carolyn U. Fisher,^* Hang Nguyen, Madhusoodana P. Nambiar,^* Vasileios Kyttaris, Arthur Weinstein, Rena Bahjat,^¶ Polly Pine,^¶ Violeta Rus,^|| and George C. Tsokos³

^*Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; Rheumatology Service, Walter Reed Army Medical Center, Washington, D.C. 20307; Section of Rheumatology, Washington Hospital Center, Washington, D.C. 20010; ^¶Rigel Pharmaceuticals, South San Francisco, CA 94080; ^||Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201

Diminished expression of TCR and reciprocal up-regulation and association of FcR 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 FcR 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-1 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI42269. The opinions expressed herein are the private ones of the authors and they do not represent those of the Department of Defense or the Department of the Army.

² S.K., Y.-T.J., and B.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. George C. Tsokos, Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115. E-mail address: gtsokos{at}bidmc.harvard.edu

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; LAT, linker for activation of T cells; PLC-1, phospholipase C-1; PVDF, polyvinylidene diflouride; RA, rheumatoid arthritis; SS, Sjögren’s syndrome; SLEDAI, SLE disease activity index; Syk, spleen tyrosine kinase.

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