Immunology
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George Tsokos

Harvard Medical School
Chief, Division of Rheumatology
Beth Israel Deaconess Medical Center
Phone: (617) 667-0751
Fax: (617) 975-5299
email: gtsokos@bidmc.harvard.edu

9 postdoctoral fellows

Tsokos

The Tsokos laboratory is interested in studies of immune cell signaling and gene transcription in human 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.

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.

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. CREMalpha activation and binding to the IL-2 promoter was found to be caused by CaMKIV 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.

4. Development of T cell-based biomarkers for SLE. While performing our studies we have identified markers that we plan to develop as biomarkers. Specifically, aggregated lipid rafts on the surface membrane of SLE T cells represent a disease specific and highly sensitive phenomenon. Expression of aggregated lipid rafts and molecules that are included in the rafts, such as FcRgamma, Syk, CD44, and complement components, is being studied with a goal of using them as disease biomarkers.

5. 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. The goal of these studies is to decipher mechanisms of tissue injury and develop approaches to limit damage.

Papers & Publications:

  1. Tenbrock, K., Kyttaris, V. C., Ahlmann, M., Ehrchen, J. M., Tolnay, M., Melkonyan, H., Mawrin, C., Roth, J., Sorg, C., Juang, Y. T. and Tsokos, G. C. (2005). The cAMP response element modulator regulates the transcription of the T cell receptor ζ chain. J. Immunol. 146: 5975-5980.
  2. Tenbrock, K., Juang, Y. T., Leukert, N., Sorg, C., Roth, J., and Tsokos, G. C. (2006). The transcriptional repressor CREM alpha recruits HDAC1 to IL-2 and c-Fos gene promoters and represses their activity. J. Immunol. 177: 6159-6164.
  3. Chowdhury, B., Krishnan, S., Tsokos, G. C., Robertson, J W., Fisher, C. U., Nambiar, M. P., and Tsokos, G. C. (2006). Expression, stability and translation of T-cell receptor z mRNA are regulated by the au-rich elements in splice deleted 3’ untranslated region of z chain. J. Immunol. 177: 8248-8257. Highlighted - In This Issue: J. Immunol. 177: 7481.
  4. Kyttaris, V. C., Juang, Y. T., Weinstein, A., Tsokos, G. C. (2007). Increased levels of NFATc2 differentially regulate CD40L and interleukin-2 genes in T cells from patients with systemic lupus erythematosus. J. Immunol. 178: 1969-1966.
  5. Li, Y., Harada, T., Juang, Y. T., Kyttaris, V. C., Wang, Y., Zidanic, M., Tung, K., and Tsokos, G. C. (2007). Anti-CD3/TCR autoantibodies induce p-ERM and trigger T cell polarization, adhesion and migration into inflamed SLE kidney. J. Immunol. 178: 1938-1947. Highlighted In This Issue, J. Immunol, 178:1226.