Immunology Faculty Member - George Tsokos, MD

George Tsokos, MD

Beth Israel Deaconess Medical Center
330 Brookline Ave.
Center for Life Sciences, Rm. 937
Boston, MA 02115
Tel: 617-735-4161
Fax: 617-735-4170

The Tsokos laboratory is interested in studies of immune cell signaling and gene transcription in human systemic lupus erythematosus (SLE), as well as in mechanisms of tissue injury. By exploring the molecular origin of the multiple immune cell abnormalities in SLE, the studies identify novel biomarkers for the diagnosis of the disease and therapeutic targets. The laboratory carries out unique studies using peripheral blood immune cells from patients with SLE and other autoimmune diseases and mice manipulated genetically to serve discoveries made patients.

1. Studies on SLE T cell signaling. SLE T cells express decreased increased T cell receptor (TCR)-mediated early signaling response. Lipid rafts are aggregated on the surface membrane of T cells while the TCR is rewired with the FcRgamma chain assuming the function of the zeta chain. Additional signaling molecules are present in the lipid rafts including Syk and the adhesion molecule CD44 which signals though pERM. pERM is phosphorylated by Rho kinase. Reconstitution of the missing CD3zeta chain, inhibition of its degradation, inhibition of Syk or Rho kinase activity all result in normalization of T cell effector function. Current studies use CD3zeta or Syk conditional knock out mice to define how these molecules contribute to disease.

2. Studies on the decreased production of interleukin-2 (IL-2) in human SLE T cells. We have established that decreased transcriptional activity of the IL-2 promotes leads to decreased production of IL-2 by SLE T cells. We have found that the suppressor CREMalpha is expressed in increased amounts in SLE T cells and binds to the IL-2 promoter. After binding, CREMalpha recruits HDAC1, which deacetylates histones and confers a "closed" chromatin structure across the
IL-2 locus . CREMalpha activation and binding to the IL-2 promoter was found to be caused by CaMK4 which is also increased in SLE T cells. In parallel studies we found that SLE T cells express increased amounts of PP2Ac which dephosphorylates CREB and thus deprives the IL-2 promoter of a putative transcriptional enhancer. Novel lupus prone mice which lack CaMK4 or CREMa or normal mice which overexpress PP2A in T cells are used to further define the role of each molecule in the expression of autoimmunity and organ damage.

3. IL23/IL17 axis in SLE - Double negative (CD3+CD4-CD8-) T cells are expanded in SLE patients and we found to produce IL-17 and more interestingly to populate the kidneys of patients with lupus nephritis. In humans, double negative T cells appear to arise from CD8+ cells and in mice they expand under the influence of IL23. Ongoing studies in humans and in genetically engineered mice will determine the origin, developmental requirements and pathogenicity of double negative cells.

4. Tissue Injury Program. We have demonstrated, using a mouse model of mesenteric ischemia/reperfusion (I/R) model that autoantibodies such, as anti-DNA, cardiolipin, histones and RNP, infused in mice resistant to RI, Rag1-/-, do not cause any tissue injury unless the mice undergo I/R. We have shown that these antibodies bind to neoantigens expressed on IR-stressed tissues, activate complement and execute pathology. We have identified the cellular components that are involved in the expression of local and remote tissue injury and current studies dissect cytokine and molecular pathways that are involved. Specifically, emphasis is given to IL-17, the activation of the inflammasome and molecular mechanism that lead to vascular leakage. The goal of these studies is to decipher mechanisms of tissue injury and develop approaches to limit damage.

Last Update: 7/24/2014


1. Tsokos, G. C. (2011). Disease Pathogenesis: Systemic lupus erythematosus. N. Engl. J. Med. 365:2110-21.

2. Crispin, J. C. Apostolidis, S. Finnell, M. and
Tsokos, G. C. (2011). Induction of PP2A B, a novel regulator of IL-2 deprivation-induced T cell apoptosis, is deficient in systemic lupus erythematosus. Proc. Natl. Aca. Sci. USA.108: 12443-12448.

3. Hedrich C. M., Crispin, J. C. Rauen, T., Ioannidis, C., Lo, M. S., Kyttaris, V. C., and
Tsokos, G. C. (2012). cAMP responsive element modulator (CREM)a mediates CpG-DNA methylation of IL-2 and IL17A during CD4 lineage commitment and contributes to T cells subset distribution in SLE. Proc. Natl. Aca. Sci. USA. 109:16606-11.

4. Moulton, V. R., Grammatikos, A.P., Fitzgerald, L. M.,
Tsokos, G. C. (2013). The splicing fector SF2/ASF rescues IL-2 production in T cells from SLE patients by activating IL-2 transcription. Proc. Natl. Aca. Sci. USA. 110(5):1845-5.

5. Kannan, L., Kis-Toth, K., Yoshiya, K., Sehrawa, S., Dalle Lucca, J. J. Thai, T. H., Mayadas, T.,
Tsokos, G. C. (2013). R-spondin3 protects intestinal tissue from ischemia/reperfusion-induced injury by preventing vascular leakage. Proc. Natl. Aca. Sci (USA). 2013 Aug 13. [Epub ahead of print]

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