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. Full text: 2011-tsokos-nejm.pdf 

 

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.
  5. Pan W, Tsokos MG, Li W, Tsokos GC. (2025). Protein phosphatases in systemic autoimmunity. Immunometabolism (Cobham). 2025 Feb 10;7(1):e00056. doi: 10.1097/IN9.0000000000000056.

 

  • 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

 

  • Bhargava, R., Li, H., Maeda, K., Tsokos, M. G., & Tsokos, G. C. (2025). Calcium calmodulin kinase IV deficiency in podocytes prevents the development of lupus nephritis.. Clinical Immunology (Orlando, Fla.), 271, 110427. https://doi.org/10.1016/j.clim.2025.110427 (Original work published 2025)
    Publisher's Version

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread organ involvement including the kidney. Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to conrol immune cell nad podocyte function. To address the effect of genetic podocyte-specific CaMK4 deficiency on systemic autoimmunity and kidney pathology in lupus-prone mice we generated B6.lpr.Camk4flox..podocincre mice. Although podocyte-specific CaMK4 deletion in the lupus-prone Br.lpr mice did not affect systemic autoimmune response parameters, it led to significant improvement of kidney pathology and clinical outcomes. Specifically, B6.lpr.Camk4flox..podocincre mice exhibited reduced glomerular pathology, characterized by less mesangial cell proliferation and diminished immune complex deposition, accompanied by decreased levels of albuminuria and improved creatinine levels. CaMK4 deficiency in podocytes averted the deposition of immune complexes in the kidney. Interestingly, we found increased deposition of immune complexes in the liver. We conclude that CaMK4 expression in podocytes is central to the development of LN and its targeted deletion in podocytes prevents its development without affecting systemic autoimmunity while immune complexes appear to be re-directed from the kidney to the liver.

  • Li, W., Kolios, A. G. A., Pan, W., Burbano, C., Karino, K., Vichos, T., Humbel, M., Kyttaris, V. C., Tsokos, M. G., & Tsokos, G. C. (2025). Gluconolactone restores immune regulation and alleviates skin inflammation in lupus-prone mice and in patients with cutaneous lupus.. Science Translational Medicine, 17(786), eadp4447. https://doi.org/10.1126/scitranslmed.adp4447 (Original work published 2025)
    Publisher's Version

    Systemic lupus erythematosus (SLE) is characterized by dysfunctional regulatory T cells (Tregs). We previously showed that protein phosphatase 2A (PP2A) plays a critical role in maintaining the suppressive function of Tregs. Here, we analyzed phosphoproteomics and metabolomics data from PP2A-wild type and PP2A-deficient Tregs and demonstrated that PP2A regulates Treg function through the pentose phosphate pathway (PPP). Furthermore, we proved that the PPP metabolite gluconolactone (GDL) enhances in vitro induced (i)Treg differentiation and function by promoting forkhead box protein 3 and phosphorylated signal transducer and activator of transcription 5 expression and inhibits T helper 17 (TH17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting TH17 cells. GDL promotes Tregs function and alleviates skin lesions in MRL.lpr lupus-prone mice in vivo. It also promotes Tregs differentiation and function in ex vivo experiments using cells from patients with SLE. Last, in patients suffering from cutaneous lupus erythematosus, topical application of a GDL-containing cream controlled skin inflammation and improved the clinical and histologic appearance of the skin lesions within 2 weeks. Together, we have identified GDL as a PPP metabolite and showed mechanistically that it restores immune regulation in vitro and in vivo by inducing Treg suppressive function and inhibiting TH17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.

  • Pan, W., Tsokos, M. G., Li, W., & Tsokos, G. C. (2025). Protein phosphatases in systemic autoimmunity.. Immunometabolism (Cobham, Surrey), 7(1), e00056. https://doi.org/10.1097/IN9.0000000000000056 (Original work published 2025)
    Publisher's Version

    Protein phosphatases play a critical role in maintaining immune homeostasis by regulating various signaling pathways involved in immune cell activation, differentiation, and function. In the context of systemic autoimmune diseases, dysregulation of phosphatase activity contributes to aberrant immune responses, leading to chronic inflammation and tissue damage. This review explores the role of key phosphatases from the protein serine/threonine phosphatase and protein tyrosine phosphatase families that are implicated in systemic autoimmunity. We discuss their diverse roles in immune cell subsets, the mechanisms by which their dysregulation drives autoimmune pathogenesis, and the therapeutic potential of targeting these enzymes.

  • Fluder, N. W., Humbel, M., Recazens, E., Jourdain, A. A., Ribi, C., Tsokos, G. C., & Comte, D. (2025). Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.. MedRxiv : The Preprint Server for Health Sciences. https://doi.org/10.1101/2025.01.28.25321013 (Original work published 2025)
    Publisher's Version

    OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells, essential for immune surveillance, exhibit profound dysfunction in SLE, including impaired cytotoxicity and cytokine production. However, the mechanisms underlying these abnormalities remain poorly understood. This study investigates how the accumulation of dysfunctional mitochondria due to defective mitophagy contributes to NK cell impairment in SLE and explores strategies to restore their function.

    METHODS: Mitochondrial structure and function in NK cells from SLE patients (n=104) and healthy controls (n=104) were assessed using flow cytometry, transmission electron microscopy, and proteomics. Mitophagy-related gene expression was quantified by RT-qPCR. The effects of Urolithin A, a mitophagy activator, and hydroxychloroquine (HCQ) on mitochondrial recycling and NK cell function were evaluated in vitro .

    RESULTS: SLE NK cells exhibited accumulation of enlarged, dysfunctional mitochondria, impaired lysosomal acidification, and increased cytosolic mitochondrial DNA leakage, consistent with defective mitophagy. Proteomic and transcriptional analyses revealed downregulation of key mitophagy-related genes. These abnormalities were associated with diminished NK cell effector functions, including reduced degranulation and cytokine production. In vitro , treatment with Urolithin A enhanced mitophagy, improved mitochondrial and lysosomal function, and restored NK cell effector responses. HCQ was also associated with partial recovery of mitochondrial recycling and NK cell function.

    CONCLUSION: These findings identify mitochondrial dysfunction and impaired mitophagy as major contributors to NK cell abnormalities in SLE. By uncovering a novel immunometabolic mechanism, this offers new insight into SLE pathogenesis and highlights potential therapeutic strategies targeting mitochondrial quality control.

  • Bhargava, R., Upadhyay, R., Zhao, C., Katakam, P., Wenderfer, S., Chen, J., He, H., Cummings, R., Tsokos, M. G., & Tsokos, G. C. (2025). Aberrant Glycosylation of IgG in Children With Active Lupus Nephritis Alters Podocyte Metabolism and Causes Podocyte Injury.. Arthritis & Rheumatology (Hoboken, N.J.). https://doi.org/10.1002/art.43200 (Original work published 2025)
    Publisher's Version

    OBJECTIVE: Podocytes are integral to the maintenance of the glomerular filtration barrier. Their injury results in proteinuria and disease progression in lupus nephritis (LN). Aberrant IgG glycosylation drives podocyte injury in LN and leads to cytoskeletal rearrangement, motility changes, and decreased nephrin production. Based on these findings, we hypothesized that IgG glycosylation patterns differentiate systemic lupus erythematosus (SLE) with and without LN and that this aberrant glycosylation reprograms podocyte metabolism.

    METHODS: IgG was isolated from 40 pediatric SLE and from 7 healthy control samples. N-glycan analysis was performed using mass spectrometry. IgG deglycosylation was performed through enzymatic treatment by Peptide N-Glycosidase F for functional studies in podocytes. Untargeted metabolomics was performed in cultured podocytes after exposure to healthy IgG, LN-derived IgG, or deglycosylated LN-IgG and analyzed by metabolite set enrichment analysis. Digital droplet polymerase chain reaction was used to evaluate urine cells and podocytes in culture for pyruvate kinase expression.

    RESULTS: The glycosylation pattern of IgG from children with LN was different from that in children with SLE without kidney involvement. Successful treatment led to normalization of IgG glycosylation. Cultured podocytes treated with LN-derived IgG had a lower rate of glycolysis compared to podocytes incubated with deglycosylated LN-IgG or IgG from healthy volunteers. Untargeted metabolomics of podocytes revealed glycolysis as the most enriched pathway in LN and identified five key metabolites (pyruvic acid, phosphoenolpyruvic acid, 2-phosoglycerate, 3 phosphoglycerate, and fructose 1,6 bisphosphate) in which their levels significantly differed among podocytes exposed to LN-derived IgG (LN-IgG) compared to healthy IgG and deglycosylated LN-IgG. This analysis also revealed clustering around a rate limiting step of glycolysis catalyzed by PKM (Pyruvate Kinase M). Urine analyses revealed elevated pyruvic acid and greater expression of pyruvate kinase in podocytes shed in urine in patients with LN compared to levels in patients with SLE without kidney involvement. Podocytes in culture had elevated PKM levels when exposed to LN-IgG compared to IgG from patients with nonrenal SLE and LN in remission.

    CONCLUSION: Aberrant IgG glycosylation develops in children with LN and adversely alters podocyte metabolism, rendering these cells vulnerable to injury. Successful treatment reverses IgG glycosylation to patterns comparable to those in patients with nonrenal SLE. These data lay a strong foundation for larger translational studies evaluating the potential of IgG glycosylation as a predictive and pharmacodynamic biomarker for LN. This work also supports a need for the development of approaches to control the aberrant glycosylation of self-targeting IgG in patients with LN as a mechanism to minimize podocytopathy.

  • Zhang, H., Sabiu, G., Jung, S., Podestà, M. A., Zhao, J., Gempler, M., Yamamura, M., Miao, J., Tsokos, G. C., Karadagi, A., Kawai, T., Abdi, R., & Sage, P. T. (2025). Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.. Kidney International, 108(1), 48-56. https://doi.org/10.1016/j.kint.2025.03.017 (Original work published 2025)
    Publisher's Version

    INTRODUCTION: Antibody-mediated rejection (ABMR) after allogeneic kidney transplantation is a substantial clinical problem for which there are no specific treatments. High endothelial venules (HEV) are specialized veins which are normally present only in lymph nodes (LN) facilitating immune cell entry. Here, we show that kidneys undergoing rejection develop HEV-like structures derived from host cells.

    METHODS: We developed a nano-delivery system targeting HEVs to simultaneously deliver therapeutics to draining LN and kidney allografts.

    RESULTS: Using this system, we preferentially delivered IL-21 neutralizing antibody (NP-HEV[αIL21]) to draining LN and kidney allografts resulting in improved graft function and recipient survival. The NP-HEV[αIL21] system also decreased alloreactive B cell responses, donor-specific antibody production, and ABMR-like lesions in kidney grafts.

    CONCLUSIONS: Our study provides a therapeutic strategy to selectively target distinct effector sites to attenuate B-cell alloimmunity while limiting effects of broad systemic immunosuppression in kidney transplantation.