Research

Job opportunity

Post-doctoral research scholar position is available In the Tsokos Lab. Self-motivated scholars that demonstrate a passion for research along with a comprehensive working knowledge of common laboratory techniques in Immunology are encouraged to apply. Expertise in flow cytometry and molecular biology and bioinformatics is desired. A PhD or MD/PhD in a relevant field is required. Fluency in English, strong communication skills and the ability to work independently as well as within a team of colleagues are also essential. Successful candidates will benefit from a dynamic and highly collaborative environment and the opportunity to interact with the extended scientific community at HMS. To be considered for the position please send a letter of interest and your CV to George C. Tsokos (gtsokos@bidmc.havard.edu).

Research Area

Pathogenesis of systemic lupus erythematosus

Our research has focused on the cellular and molecular pathogenesis of systemic lupus erythematosus (SLE). We opened and led the field of molecular abnormalities on immune cells in patients with SLE. Our laboratory performs biochemical, molecular biology and cellular studies of immune and kidney cells using human material and genetically engineered mice.  Molecules that are identified to contribute to immune cell malfunction are further exploited by constructing normal or lupus-prone mice engineered to express or lack each molecule to confirm their significance in vivo.  A number of targets have entered or are considered to enter clinical trials by pharma. More recently we conduct studies to understand how immune elements interact with kidney resident cells. We have been uncovering mechanisms whereby resident cells through specific molecular pathways determine whether, in the context of autoimmunity, inflammation and damage will occur.

Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011 Dec 1;365(22):2110-21.

Pathogenesis of SLE

Individual Projects

  • Aberrant early lymphocyte signaling in SLE.  T lymphocytes from patients with SLE display increased and aberrant early signaling response because the T cell receptor is “rewired”. 
  1.   Liossis, S. N. C., Ding, X. Z., Dennis, G. J. and Tsokos, G. C.  (1998).  Altered TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of T-cell receptor z chain.  J. Clin Invest. 101:1448-1457. PMC508723.
  2. Moulton, V. R., Grammatikos, A.P., Fitzgerald, L. M., Tsokos, G. C. (2013). The splicing factor 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. PMC3562779
  3. Katsuyama, E., Suarez-Fueyo, A., Bradley, S. J., Kono, M., Kyttaris, V. C., Mizui, M., Mulki, L., Malavasi, F., Tsokos. G. C.  (2020). CD38 expression in CD8 T cells compromises cytotoxic function and identifies patients with systemic lupus erythematosus prone to infections. Cell Reports. 30: 112-123.
  4. Chen, P.M., Katsuyama, E., Satyam, A., Li, H., Rubio, J., Jung, S., Andrzejewski, Becherer, D., Tsokos, M. G., Abdi, R., Tsokos, G. C. (2022). CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.  Science Adv. 2022 Jun 17;8(24):eabo4271.

 

 

 

 

  • cAMP response element modulator alpha.  A gene and function study unveils the molecular underpinnings of antithetic production of IL-2 and IL-17 in SLE. 
  1. 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. PMC3478624.
  2. Yoshida, N., Comte, D., Mizui, M., Otomo, K., Rosetti, F., Mayadas, T. N., Crispín, J. C., Bradley, S., Koga, T., Kono, M., Tenbrock, K., Karampetsou, M., Kyttaris, V. C., and Tsokos, G. C.  (2016). ICER controls Th17 cell differentiation and regulates autoimmune pathology. Nature Commun. 29;7:12993. doi: 10.1038/ncomms12993. 
  3. Kono, M., Yoshida, N., Maeda, K.,  Tsokos, G. C. (2018). Transcriptional factor ICER promotes Glutaminolysis and the generation of Th17 cells. Proc. Natl. Aca. Sci. USA. 115(10):2478-2483.
  4. Li,  P., Jiang, M., Li, K., Xiao, X., Zhou, Y., Li, H., Xu, Y., Krisfield, S, Lipsky, P. E., Tsokos, G.C. (corresponding author),  Zhang, X. (2021). Glutathione peroxidase 4 regulated neutrophil ferroptosis induces systemic autoimmunity. Nature Immunol. 22(9):1107-1117. Research highlights in:  Ohl, K., Rauen, T., Tenbrock, K., Dysregulated neutrophilic cell death in SLE: a spotlight on ferroptosis.  Signal Transduction and Targeted Therapy (2021)6:392;Pan, Z., Naowarojna, N., Wang, Y. et al. Neutrophil ferroptotic death promotes autoimmune pathogenesis. Sci. China Life Sci. (2021). https://doi.org/10.1007/s11427-021-2014-4; Mao, C., Lei, G., Zhuang, L., Gan, B. Ferroptosis as an important driver of lupus. Protein & Cell, https://doi.org/10.1007/s13238-021-00892-1

 

 

  • Double Negative (DN) Cells.   CD3positive but CD4 and CD8 negative T cells are expanded in patients with SLE and provide help to B cells to produce anti-DNA antibodies and produce IL-17 and infiltrate the kidney
  1. Hedrich, C. M., Crispin, J. C., Rauen, T., Ioannidis, C., Koga, T., Rodriguez Rodriguez, N., Apostolidis, S. A., Kyttaris, V. C., Tsokos, G. C.   (2014).  cAMP responsive element modulator (CREM)α mediates chromatin remodeling of CD8 during the generation of CD3+CD4-CD8- T cells.  J. Biol. Chem. 289(4):2361-70. PMC3900979
  2. Li, H., Tsokos, M. G., Bickerton, S., Sharabi, A., Li, Y., Moulton, V. R. Fahmy, T. M., Tsokos, G. C. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI (Insight) doi.org/101172/jci.insight.120880.
  3. Li H, Adamopoulos IE, Moulton VR, Stillman IE, Herbert Z, Moon JJ, Sharabi A, Krishfield S, Tsokos MG, Tsokos GC. Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells. Nature Commun. 2020 Jun 5;11(1):2859. doi: 10.1038/s41467-020-16636-4. PubMed PMID: 32503973.
  4. Li, H., Tsokos, M. G., Bhargava, R., Adamopoulos, I. E., Menn-Josephy, H., Stillman, I, E., Jordan, J., Rosenstiel, P.,  Tsokos, G. C.  IL-23 acts renal tubular epithelial cells to drive lymphoid follicle formation in the kidney independent of IL-17.  J. Clin. Invest. 2021 May 6:142428. doi: 10.1172/JCI142428

 

 

  • Calcium Calmodulin Kinase 4 in SLE. A treatment target - CaMK4 is increased in SLE T cells and tissue resident cells.
  1. Juang, Y. T., Wang, Y., Solomou, E. E., Mawrin, C., Tenbrock, K., Kyttaris, V. C., and Tsokos, G. C.  (2005). Systemic lupus erythematosus serum Ig increases CREM binding to the IL-2 promoter and suppress IL-2 production through CaMKIV.  J. Clin. Invest. 115: 996-1005. PMC1070410.
  2. Koga, T., Hedrich, C., Mizui, M., Yoshida, N., Lieberman, L. A., Rauen, T., Crispín, J. C.  Tsokos, G. C. (2014). CaMK4 promotes TH17 related autoimmune pathology though Akt/mTOR and CREM-a.  J. Clin. Invest. 124(5):2234-45. PMC4001553.
  3. Maeda, K., Otomo, K., Yoshida, N., Abu-Asab, A. S., Ichinose, K., Nishino, T., Kono, M., Ferretti, A., Maruyama, S., Bickerton, S., Fahmy, T. M., Tsokos, M. G., Tsokos, G. C. 2018. Podocyte-specific delivery of calcium/calmodulin kinase inhibitor prevents autoimmune and drug-induced kidney damage.  J. Clin. Invest. 128(8):3445-345.
  4. Scherlinger, M., Pan, W., Hisada, R., Boulougoura, A., Yoshida, N., Vukelic, M., Umeda, M., Krishfield, S., Tsokos, M. G., Tsokos, G. C. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function and stability in systemic autoimmunity. Science Adv. 8, eadc9657 (2022)
  5. Scherlinger M, Li H, Pan W, Li W, Karino K, Vichos T, Boulougoura A, Yoshida N, Tsokos MG, Tsokos GC. CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses. Nat Commun. 2024;15(1):840.

 

 

Media Select

  • The first Ser/Thr Phosphatase (PP2A) in autoimmunity. 
  1. Katsiari, C. G., Kyttaris, V. C., Juang, Y. T. and Tsokos, G. C.   (2005).  Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J. Clin. Invest. 115: 3193–3204 PMC1253625
  2. Crispin, J. C. Apostolidis, S. Finnell, M. and Tsokos, G. C. (2011). Induction of PP2A Bb, 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. PMC3145691
  3. Apostolidis, S. A., Rodriguez-Rodriguez, N., Fueyo-Suarez, A., Dioufa, N., Crispin, J. C., Ezcan, E., Tsokos, M. and Tsokos, G. C.  (2016).  Protein phosphatase 2a is requisite for the function of regulatory T cells.  Nature Immunol.  17; 556- 564.    Commentary by G. M. Delgoffe PP2A’s restraint on mTOR is critical for Treg cell activity.Nature Immunol. 17: 478-479.  Commentary in The Rheumatologist.
  4. Pan, W., Nagpal, K., Suarez-Fueyo, A., Ferretti, A., Tsokos, M. G., Tsokos, G. C. (2021). The regulatory subunit PPP2R2A of PP2A enhances Th1 and Th17 differentiation through activation of the GEF-H1/RhoA/ROCK signaling pathway. J. Immunol.  206(8):1719-1728

 

 

 

  • Immunopathogenesis of lupus neprhritis. Little is known about the pathogenesis of lupus nephritis (LN), particularly as it relates to the initiation and propagation of the inflammatory response which accounts for the development or end stage renal disease. LN may complicate up to two thirds of patients with systemic lupus erythematosus with higher rates commonly seen among minorities and children.   Besides the needle kidney biopsy, we lack tools that reflect tissue pathology with fidelity. Although two drugs have been recently approved to treat patients with LN, all treatment protocols involve systemic administration of drugs or biologics which are laden with side effects and limited clinical efficacy.    Ample evidence has revealed that kidney resident cells and newly formed high endothelial venules in the presence of an autoinflammatory environment, upregulate molecules which account for the ensuing inflammation and cell damage, while in their absence, kidney damage is averted.  These molecular changes can be recorded in parallel in podocytes and tubular epithelial cells in the urine.  This project will test the hypothesis that interaction of constituents of the immune system with kidney resident cells and the  ectopically formed high endothelial venules, determines the development of inflammation and injury in the setting of LN: 1) Interplay between autoimmune effectors and kidney resident cells in lupus nephritis and 2) Newly formed high endothelial cells in the kidney- pathogenesis and implications in lupus nephritis.

a. Tsokos, G. C. Autoimmunity and organ damage in systemic autoimmunity.  Nature Immunol.  21, 605-614, 2020.

b. Tsokos, G. C.  Boulougoura, A., Kasinath, V., Abdi, R., Li, H. The immunoregulatory roles of non-haematopoietic cells in the kidney. Nature Rev. Nephrol. 2023 Nov 20. doi: 10.1038/s41581-023-00786-x

 

 

 

  • Tsokos, G. C. (2024). The immunology of systemic lupus erythematosus. Nature Immunology, 25(8), 1332-1343. https://doi.org/10.1038/s41590-024-01898-7 (Original work published 2024)
    Publisher's Version

    Understanding the pathogenesis and clinical manifestations of systemic lupus erythematosus (SLE) has been a great challenge. Reductionist approaches to understand the nature of the disease have identified many pathogenetic contributors that parallel clinical heterogeneity. This Review outlines the immunological control of SLE and looks to experimental tools and approaches that are improving our understanding of the complex contribution of interacting genetics, environment, sex and immunoregulatory factors and their interface with processes inherent to tissue parenchymal cells. Efforts to advance precision medicine in the care of patients with SLE along with treatment strategies to correct the immune system hold hope and are also examined.

  • Pan, W., & Tsokos, G. C. (2024). Reverse aging to treat lupus. European Journal of Immunology, e2451274. https://doi.org/10.1002/eji.202451274 (Original work published 2024)
    Publisher's Version

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4+ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4+CD57+ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

  • Schmauch, E., Severin, Y., Xing, X., Mangold, A., Conrad, C., Johannsen, P., Kahlenberg, M., Mellett, M., Navarini, A., Nobbe, S., Sarkar, M. K., Satyam, A., Tsoi, L. C., French, L. E., Nilsson, J., Linna-Kuosmanen, S., Kaikkonen, M. U., Snijder, B., Kellis, M., … Kolios, A. G. A. (2024). Targeting IL-1 controls refractory pityriasis rubra pilaris. Science Advances, 10(27), eado2365. https://doi.org/10.1126/sciadv.ado2365 (Original work published 2024)
    Publisher's Version

    Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB-mediated IL-1β-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.

  • Pan, W., Tsokos, M. G., Scherlinger, M., Li, W., & Tsokos, G. C. (2024). The PP2A regulatory subunit PPP2R2A controls NAD+ biosynthesis to regulate T cell subset differentiation in systemic autoimmunity. Cell Reports, 43(7), 114379. https://doi.org/10.1016/j.celrep.2024.114379 (Original work published 2024)
    Publisher's Version

    The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.

  • Xu, M., Ito-Kureha, T., Kang, H.-S., Chernev, A., Raj, T., Hoefig, K. P., Hohn, C., Giesert, F., Wang, Y., Pan, W., Ziętara, N., Straub, T., Feederle, R., Daniel, C., Adler, B., König, J., Feske, S., Tsokos, G. C., Wurst, W., … Heissmeyer, V. (2024). The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression. Nature Communications, 15(1), 2194. https://doi.org/10.1038/s41467-024-46371-z (Original work published 2024)
    Publisher's Version

    The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

  • Alimova, M., Sidhom, E. H., Satyam, A., Dvela-Levitt, M., Melanson, M., Chamberlain, B. T., Alper, S. L., Santos, J., Gutierrez, J., Subramanian, A., Grinkevich, E., Bricio, E. R., Kim, C., Clark, A., Watts, A., Thompson, R., Marshall, J., Pablo, J. L., Coraor, J., … Greka, A. (2020). A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic. BioRxiv. https://doi.org/2020.06.30.180380 [pii]10.1101/2020.06.30.180380
    Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease arising from SARS-CoV-2 infection. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury (ALI) and respiratory distress syndrome (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo , Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro , SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury.