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Dan Hu, Ph.D.


Available: 01/01/00, Expires: 10/31/23

Proinflammatory Th17 and Th1 cells are implicated in human autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Sex differences strongly impact the prevalence of autoimmunity. We reported that transcription factor Upstream Stimulatory Factor 2 (USF2) is induced during proinflammatory Th17 differentiation and promotes proinflammatory cytokine expression, and the mRNA level of USF2 is elevated in peripheral Th17-enriched cells isolated from female RA patients resistant to anti-TNF therapy compared to female patients who respond to the treatment (Hu, D., et al., PNAS, 2020). The goal of this project is to determine the impact of USF2 on human proinflammatory Th17 and Th1 development and function in the context of sexual dimorphism. We will analyze immune capacity-relevant protein synthesis and gene expression in in vitro differentiated human Th17 and Th1 cells regulated by USF2 in the context of sexual dimorphism. The student will work together with the Principal Investigator in the lab to conduct experiments and analyze and interpret the results. Students with prior experience with flow cytometry, cell culture, ELISA, RNA isolation, qPCR analysis are encouraged to apply.

Available: 11/10/22, Expires: 03/31/25

One major immune cell type that has been implicated in the autoimmune attack in Multiple sclerosis (MS) is called a Th17 cells. There are different types of Th17 cells in terms of their ability to cause inflammation and disease. Some of them produce a potent chemical called interferon gamma and these cells are called Th1/17 cells. These cells are very inflammatory and thus have the potential to cause major damage to the brain in MS. However, the mechanism underlying the development of Th1/17 cells in MS is not well understood. We found that a protein called a “heat shock protein 70” or Hsp70 was greatly increased in Th1/17 cells isolated from MS patients, and level of the gene that makes Hsp70 returned to normal after patients received MS disease-modifying therapies. We found that the Hsp70 protein amplified the disease inducing properties of Th1/17 cells Interestingly, at the same time, the Hsp70 protein could dampen these disease inducing properties suggesting that the Hsp70 protein may be a negative regulator of Th1/17 development. We hypothesize that the balance between the pro and anti-inflammatory pathways regulated by the Hsp70 protein is critical for controlling the disease inducing properties of Th17 cells and maintaining the balance of the immune system which is disrupted in MS. Our goals are (1) to determine whether the effect of increased Hsp70 protein activity in Th1/17 cells is primarily to enhance the disease-inducing capacity of Th1/17 cells; (2) to determine the genes involved by which the Hsp70 protein regulates the disease-inducing capacity of Th1/Th17 cells and to determine whether these genes are dysregulated in MS, and (3) to determine whether the decreased Hsp70 protein activity after MS disease-modifying therapy makes these cells less inflammatory and whether this beneficial effect is not seen in patients who do not respond to the disease-modifying therapies, (4) to determine whether the increased inflammatory capacity of Th1/17 cells is associated with progression from relapsing to secondary progressive MS. We will (1) conduct sophisticated gene analysis on individual T cells isolated from MS patients and healthy controls to further define in which T cell subsets the Hsp70 protein is dysregulated in MS, (2) measure the chemical production by Hsp70 stimulated Th17 cells and how these chemicals affect other immune cells called macrophages, (3) manipulate the genes which our preliminary results suggest are involved in inducing the Hsp70 protein, determine how these genes work and determine whether these mechanisms do not function properly in MS, and (4) conduct gene analysis on individual of Th1/17 cells isolated from treated MS patients to assess their inflammatory capacity and determine if their inflammatory capacity correlates with treatment responses and disease progression.

Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Hu D, Xia W, Weiner HL. CD8+ T cells in neurodegeneration: friend or foe? Mol Neurodegener. 2022 09 02; 17(1):59. PMID: 36056406; PMCID: PMC9437386.
    Citations:    Fields:    Translation:Cells
  2. Fujiwara M, Raheja R, Garo LP, Ajay AK, Kadowaki-Saga R, Karandikar SH, Gabriely G, Krishnan R, Beynon V, Paul A, Patel A, Saxena S, Hu D, Healy BC, Chitnis T, Gandhi R, Weiner HL, Murugaiyan G. microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance. J Clin Invest. 2022 05 16; 132(10). PMID: 35298438; PMCID: PMC9106347.
    Citations:    Fields:    Translation:HumansAnimalsCells
  3. Hu D, Murugaiyan G. CD8+ Tregs kill pathogenic cells to avert autoimmunity. Trends Immunol. 2022 06; 43(6):415-416. PMID: 35527183.
    Citations:    Fields:    Translation:HumansAnimalsCells
  4. Hu D, Tjon EC, Andersson KM, Molica GM, Pham MC, Healy B, Murugaiyan G, Pochet N, Kuchroo VK, Bokarewa MI, Weiner HL. Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells. Proc Natl Acad Sci U S A. 2020 12 01; 117(48):30639-30648. PMID: 33203678.
    Citations: 7     Fields:    Translation:HumansCells
  5. Xiao S, Bod L, Pochet N, Kota SB, Hu D, Madi A, Kilpatrick J, Shi J, Ho A, Zhang H, Sobel R, Weiner HL, Strom TB, Quintana FJ, Joller N, Kuchroo VK. Checkpoint Receptor TIGIT Expressed on Tim-1+ B Cells Regulates Tissue Inflammation. Cell Rep. 2020 07 14; 32(2):107892. PMID: 32668241.
    Citations: 10     Fields:    Translation:AnimalsCells
  6. Hu D, Notarbartolo S, Croonenborghs T, Patel B, Cialic R, Yang TH, Aschenbrenner D, Andersson KM, Gattorno M, Pham M, Kivisakk P, Pierre IV, Lee Y, Kiani K, Bokarewa M, Tjon E, Pochet N, Sallusto F, Kuchroo VK, Weiner HL. Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun. 2017 11 17; 8(1):1600. PMID: 29150604; PMCID: PMC5693957.
    Citations: 41     Fields:    Translation:HumansAnimalsCells
  7. Pinyavat T, Warner DO, Flick RP, McCann ME, Andropoulos DB, Hu D, Sall JW, Spann MN, Ing C. Summary of the Update Session on Clinical Neurotoxicity Studies. J Neurosurg Anesthesiol. 2016 Oct; 28(4):356-360. PMID: 27768673.
    Citations: 10     Fields:    Translation:Humans
  8. Andersson KM, Cavallini NF, Hu D, Brisslert M, Cialic R, Valadi H, Erlandsson MC, Silfverswärd S, Pullerits R, Kuchroo VK, Weiner HL, Bokarewa MI. Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment. Mol Med. 2015 Jun 04; 21:536-43. PMID: 26062018; PMCID: PMC4607618.
    Citations: 15     Fields:    Translation:HumansCells
  9. Hu D, Weiner HL, Ritz J. Identification of cytolytic CD161- CD56+ regulatory CD8 T cells in human peripheral blood. PLoS One. 2013; 8(3):e59545. PMID: 23527216.
    Citations: 10     Fields:    Translation:HumansCells
  10. Hernandez LF, Kubota Y, Hu D, Howe MW, Lemaire N, Graybiel AM. Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons. J Neurosci. 2013 Mar 13; 33(11):4782-95. PMID: 23486949.
    Citations: 18     Fields:    Translation:Animals
  11. Lemaire N, Hernandez LF, Hu D, Kubota Y, Howe MW, Graybiel AM. Effects of dopamine depletion on LFP oscillations in striatum are task- and learning-dependent and selectively reversed by L-DOPA. Proc Natl Acad Sci U S A. 2012 Oct 30; 109(44):18126-31. PMID: 23074253.
    Citations: 38     Fields:    Translation:Animals
  12. Doss MX, Di Diego JM, Goodrow RJ, Wu Y, Cordeiro JM, Nesterenko VV, Barajas-Martínez H, Hu D, Urrutia J, Desai M, Treat JA, Sachinidis A, Antzelevitch C. Maximum diastolic potential of human induced pluripotent stem cell-derived cardiomyocytes depends critically on I(Kr). PLoS One. 2012; 7(7):e40288. PMID: 22815737.
    Citations: 72     Fields:    Translation:HumansCells
  13. Mittal A, Murugaiyan G, Beynon V, Hu D, Weiner HL. IL-27 induction of IL-21 from human CD8+ T cells induces granzyme B in an autocrine manner. Immunol Cell Biol. 2012 Sep; 90(8):831-5. PMID: 22430249.
    Citations: 14     Fields:    Translation:HumansAnimalsCells
  14. Hu D, Liu X, Zeng W, Weiner HL, Ritz J. A clonal model for human CD8+ regulatory T cells: unrestricted contact-dependent killing of activated CD4+ T cells. Eur J Immunol. 2012 Jan; 42(1):69-79. PMID: 22002875.
    Citations: 3     Fields:    Translation:HumansCells
  15. Barnes TD, Mao JB, Hu D, Kubota Y, Dreyer AA, Stamoulis C, Brown EN, Graybiel AM. Advance cueing produces enhanced action-boundary patterns of spike activity in the sensorimotor striatum. J Neurophysiol. 2011 Apr; 105(4):1861-78. PMID: 21307317.
    Citations: 10     Fields:    Translation:AnimalsCells
  16. Kubota Y, Liu J, Hu D, DeCoteau WE, Eden UT, Smith AC, Graybiel AM. Stable encoding of task structure coexists with flexible coding of task events in sensorimotor striatum. J Neurophysiol. 2009 Oct; 102(4):2142-60. PMID: 19625536.
    Citations: 35     Fields:    Translation:AnimalsCells
  17. Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H. Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity. 2007 May; 26(5):593-604. PMID: 17509909; PMCID: PMC3428267.
    Citations: 107     Fields:    Translation:AnimalsCells
  18. Barnes TD, Kubota Y, Hu D, Jin DZ, Graybiel AM. Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature. 2005 Oct 20; 437(7062):1158-61. PMID: 16237445.
    Citations: 273     Fields:    Translation:AnimalsCells
  19. Shigematsu H, Reizis B, Iwasaki H, Mizuno S, Hu D, Traver D, Leder P, Sakaguchi N, Akashi K. Plasmacytoid dendritic cells activate lymphoid-specific genetic programs irrespective of their cellular origin. Immunity. 2004 Jul; 21(1):43-53. PMID: 15345219.
    Citations: 85     Fields:    Translation:HumansAnimalsCells
  20. Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004 May; 5(5):516-23. PMID: 15098030.
    Citations: 130     Fields:    Translation:AnimalsCells
  21. Smith AC, Frank LM, Wirth S, Yanike M, Hu D, Kubota Y, Graybiel AM, Suzuki WA, Brown EN. Dynamic analysis of learning in behavioral experiments. J Neurosci. 2004 Jan 14; 24(2):447-61. PMID: 14724243; PMCID: PMC6729979.
    Citations: 120     Fields:    Translation:Animals
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.