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
Email: gtsokos@bidmc.harvard.edu



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: 7/9/2015



Publications

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


2. Hedrich C. C., Rauen, T., Apostolidis, S. A. Grammatikos, A. P., Rodriguez-Rodriguez, N., Ioannidis, C., Kyttaris, V. C., Crispin, J. C. and Tsokos, G. C. (2014). Increased Stat3 phosphorylation promotes IL-10 expression in SLE T cells through trans-activation and chromatin remodeling. Proc. Natl. Aca. Sci. (USA). 111(37):13457-62

3. Muroya, T., Kannan, L., Ghiran, I. C., Shevkoplyas, S. S., Paz, Z., Tsokos, M., Dalle Lucca, |J. J., Shapiro, N. I. and Tsokos, G. C. (2104). C4d deposits on the Surface Membrane of Red Blood Cells in Trauma Patients and Interferes with their Function. Crit. Care Med. 42(5):e364-72.

4. Koga, T., Hedrich, C., Mizui, M., Yoshida, N., Lieberman, L. A., Rauen, T., Crispín, J. C. and Tsokos, G. C. (2014). CaMK4 promotes TH17 related autoimmune pathology though Akt/mTOR and CREM-a. J. Clin. Invest. 124(5):2234-45.

5. Moulton, V. and Tsokos, G. C. (2015). T cell signaling abnormalities in systemic autoimmunity explain aberrant immune cell function and provide rational targets for treatment. J. Clin. Invest., 125(6):2220-7.



© 2015 by the President and Fellows of Harvard College