Tsokos Lab: Research

George C. Tsokos, M.D. Laboratory

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.

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.

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 promoter 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.  We use lupus-prone mice to carry our preclinical studies and we engineer genetically lupus-prone animals (e.g. MRL/lprCamkiv-/-) to confirm findings in patients with SLE and better dissect the involved mechanisms.

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.

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.

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.

Recent Publications

1. Chen J, Crispin JC, Dalle Lucca J, Tsokos GC. A Novel Inhibitorof the Alternative Pathway of Complement Attenuates IntestinalIschemia/Reperfusion-Induced Injury. J Surg Res. 2009 Jun25. [Epubahead of print]
2. Zhang Z, Kyttaris VC, Tsokos GC. The role of IL-23/IL-17 axis in lupus nephritis. J Immunol. 2009;183:3160-3169. Epub 2009 Aug 5
3. Kulik L, Fleming SD, Moratz C, Reuter JW, Novikov A, Chen K,Andrews KA, Markaryan A, Quigg RJ, Silverman GJ, Tsokos GC, Holers VM.Pathogenic natural antibodies recognizing annexin IV are required todevelop intestinal ischemia-reperfusion injury. J Immunol.2009;182:5363-5373
4. Chen J, Crispin JC, Tedder TF, Dalle Lucca J, Tsokos GC. B cellscontribute to ischemia/reperfusion-mediated tissue injury. J Autoimmun.2009;32:195-200
5. Shi T, Moulton VR, Lapchak PH, Deng GM, Dalle Lucca JJ, TsokosGC. Ischemia-mediated aggregation of the actin cytoskeleton is one ofthe major initial events resulting in ischemia-reperfusion injury. Am JPhysiol Gastrointest Liver Physiol. 2009;296:G339-347
6. Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, StillmanIE, Kyttaris VC, Juang YT, Tsokos GC. Expanded double negative T cellsin patients with systemic lupus erythematosus produce IL-17 andinfiltrate the kidneys. J Immunol. 2008;181:8761-8766
7. Krishnan S, Juang YT, Chowdhury B, Magilavy A, Fisher CU, NguyenH, Nambiar MP, Kyttaris V, Weinstein A, Bahjat R, Pine P, Rus V, TsokosGC. Differential expression and molecular associations of Syk insystemic lupus erythematosus T cells. J Immunol. 2008;181:8145-8152
8. Deng GM, Tsokos GC. Cholera toxin B accelerates diseaseprogression in lupus-prone mice by promoting lipid raft aggregation. JImmunol. 2008;181:4019-4026
9. Moulton VR, Kyttaris VC, Juang YT, Chowdhury B, Tsokos GC. TheRNA-stabilizing protein HuR regulates the expression of zeta chain ofthe human T cell receptor-associated CD3 complex. J Biol Chem.2008;283:20037-20044
10. Crispin JC, Kyttaris VC, Juang YT, Tsokos GC. How signaling andgene transcription aberrations dictate the systemic lupus erythematosusT cell phenotype. Trends Immunol. 2008;29:110-115
11. Katsiari CG, Kyttaris VC, Juang YT, Tsokos GC. Proteinphosphatase 2A is a negative regulator of IL-2 production in patientswith systemic lupus erythematosus. J Clin Invest. 2005;115:3193-3204

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