Thomas C. Mitchell, Ph.D.

Education:

B.S., Biology, University of Michigan, Ann Arbor MI; Sept 1982–May 1986
Ph.D., Molecular Biology of Retroviruses, University of Wisconsin-Madison, Madison WI; Sept 1986–Dec 1992
Postdoctoral Fellowship, training in DNA tumor virology, University of Wisconsin-Madison, Madison WI; Jan 1993–Feb 1995
Postdoctoral Fellowship, training in immunology, Howard Hughes Medical Institute, National Jewish Medical Research Center, Denver CO; Mar 1995–Sept 2000

Curriculum Vitae 

Current Positions: 

Professor of Microbiology and Immunology, University of Louisville
Barnstable-Brown Gala Chair in Diabetes Research, University of Louisville
Member, James Graham Brown Cancer Center

Contact Information: 

Clinical & Translational Research Building
505 South Hancock Street
University of Louisville
Louisville, KY 40202
Phone:  502/852-2073
Email:  tom.mitchell@louisville.edu

Research Description: 

My current NIH-funded research is focused on understanding the immunology of the cervical cancer vaccine Cervarix, a second-to-market version of Gardasil.  It is funded by the NIAID through an R01 award entitled: “Mechanisms of Successful Vaccine Adjuvants”, and focuses on understanding the mechanisms by which a novel component of the Cervarix vaccine renders it superior to Gardasil in terms of the durability of protection from infection by oncogenic human papilloma viruses (HPV). This R01 project includes broader aspects of immunological priming as I anticipate studying the same novel component in the context of a varicella zoster vaccine that prevents the recurrence of herpetic shingles. Going forward, one of my interests is to understand how CD8+ T cell responses are primed against tumor antigens, and how CD8+ T cell function can be boosted to aid in CAR-T and other therapies. Another building interest is in the biology of neutrophils and how their functions in primary immune defense might be manipulated for either stronger immunity or avoidance of chronic inflammation.

In even broader terms, I consider my research to be grounded in basic immunology at the level of addressing the most fundamental question in the discipline: How does the immune system protect ‘self’ without destroying ‘self’? This balance is involved in the immune surveillance that generally keeps us protected from neoplastic cell outgrowths, that sometimes fails when the immune system begins to become tolerant of tumor masses following attempts to eradicate them, and that is the current focus of immune oncology in which various strategies are being tested to reverse tolerance so that the immune system can return to tumoricidal functions. When inverted these same questions apply to the study of autoimmune diabetes, in keeping with my endowed chair requiring relevance to diabetes research. In autoimmune diseases such as Type I diabetes, the mandate to avoid destroying ‘self’ is warped to the point that a required endocrine function is ablated and the challenge becomes that of re-balancing immune function. 

Literature Cited: 

  1. Mitchell TC, Hildeman D, Kedl R, Teague TK, Schaefer BC, White J, Zhu Y, Kappler J, Marrack P.  Immunological adjuvants promote activated T cell survival via induction of Bcl-3.  Nature Immunology 2001 May;2(5):397-402.  doi: 10.1038/87692.  PMID: 11323692.
  2. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC.  The vaccine adjuvant monophosphoryl lipid A as a trif-biased agonist of TLR4.  Science 2007 Jun 15;316(5831):1628-32.  doi: 10.1126/science.1138963.  PMID: 17569868.  This paper was highlighted in a Science Perspectives article by KA Fitzgerald and DT Golenbock titled, The Shape of Things to Come. Science 2007 Jun 15;316(5831):1574-1576.
  3. Cekic C, Casella CR, Eaves CA, Matsuzawa A, Ichijo H, Mitchell TC.  Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. Journal of Biological Chemistry 2009 Nov 13;284(46):31982-91.  doi: 10.1074/jbc.M109.046383.  Epub 2009 Sep 15. PMID: 19759006.  PMCID: PMC2797270.
  4. Li B, Cai Y, Qi C, Hansen R, Ding C, Mitchell TC, Yan J.  Orally administered particulate beta-glucan modulates tumor-capturing dendritic cells and improves antitumor T-cell responses in cancer.  Clinical Cancer Research 2010 Nov 1;16(21):5153-64.  doi: 10.1158/1078-0432.CCR-10-0820.  Epub 2010 Sep 20.  PMID: 20855461.  PMCID: PMC2970627.
  5. Cekic C, Casella CR, Sag D, Kolb J, Suttles J, Antignano F, Krystal G, Mitchell TC.  MyD88 contributes to the low toxicity of synthetic monophosphoryl lipid A through SHIP1 activation.  Journal of Immunology 2011 Apr 1;186(7):3858-65.  doi: 10.4049/jiimunol.1001034.  Epub 2011 Feb 21.  PMID: 21339365.  PMCID: PMC3249415.
  6. Embry, CA, Franchi L, Nunez G, Mitchell, TC.  Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.  Science Signaling 2011 May 3;4(171): ra28. ( www.sciencesignaling.org ). This paper was highlighted in an Editor’s Summary (http://stke.sciencemag.org/cgi/content/summary/sigtrans;4/171/ra28) and a podcast (Science Signaling Podcast: 3 May 2011, Thomas C. Mitchell and Annalisa M. VanHook, Science Signaling 4(171):pc9.
  7. Bowen WS, Minns LA, Johnson DA, Mitchell TC, Hutton MM, Evans JT.  Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.  Science Signaling 2012 Feb 14;5(211):ra13.  doi:10.1126/scisignal.2001963.  PMID: 22337809.  PMCID: PMC3684200.  
  8. Gandhapudi SK, Chilton PM, Mitchell TC.  TRIF is required for TLR4 mediated adjuvant effects on T cell clonal expansion.  PLoS One 2013;8(2):e56855.  doi: 10.1371/journal.pone.0056855.  Epub 2013 Feb 15.  PMID: 23457630.  PMCID: PMC3574014.
  9. Casella CR, Mitchell TC.  Inefficient TLR4/MD-2 heterotetramerization by monophosphoryl lipid A. PLoS One 2013 Apr 26;8(4):e62622.  doi: 10.1371/journal.pone0062622.  PMID: 23638128.  PMCID: PMC3637461.
  10. Chilton PM, Hadel DM, To TT, Mitchell TC, Darveau RP.  Adjuvant activity of naturally occurring monophosphoryl lipopolysaccharide preparations from mucosa-associated bacteria.  Infection & Immunity 2013 Sep;81(9):3317-25.  doi: 10.1128/IAI.01150-12.  Epub 2013 Jun 24.  PMID: 23798540.  PMCID: PMC3754217.    
  11. Kolb JP, Casella CR, SenGupta, S, Chilton PM, Mitchell TC.  Type I interferon signaling contributes to the bias that Toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF.  Science Signaling 2014 Nov 11;7(351):ra108.  doi: 10.1126/scisignal.2005442.  PMID: 25389373.  PMCID: PMC4459894.
  12. SenGupta S, Hittle LE, Ernst RK, Uriarte SM, Mitchell TC.  A Pseudomonas aeruginosa hepta-acylated lipid A variant associated with cystic fibrosis selectively activates human neutrophils.  Journal of Leukocyte Biology 2016 Nov;100(5):1047-59.  doi: 10.1189/jlb.4VMA0316-101R.  Epub 2016 Aug 18.  PMID: 27538572.  PMCID: PMC6608067.
  13. Bodduluri SR, Mathis S, Maturu P, Krishnan E, Satpathy SR, Chilton PM, Mitchell TC, Lira S, Locati M, Mantovani A, Jala VR, Haribabu B.  Mast cell-dependent CD8+ T-cell recruitment mediates immune surveillance of intestinal tumors in ApcMin/+ mice.  Cancer Immunology Research 2018 Mar;6(3):332-47.  doi: 10.1158/2326-6066.CIR-17-0424.  Epub 2018 Jan 30.  PMID: 29382671.  [ https://cancerimmunolres.aacrjournals.org/content/6/3/332.long ]
  14. SenGupta S, Rane MJ, Uriarte SM, Woolley C, Mitchell, TC.  Human neutrophils depend on extrinsic factors produced by monocytes for their survival response to TLR4 stimulation.  Innate Immunity 2019 Nov;25(8):473-86.  doi: 10.1177/1753424929871994.  Epub 2019 Sep 3.  PMID: 31480890.  PMCID: PMC6900669.
  15. Wang YQ, Bazin-Lee H, Evans JT, Casella CR, Mitchell TC.  MPL adjuvant contains competitive antagonists of human TLR4.  Frontiers in Immunology 2020 Oct 16;11:577823.  doi: 10.3389/fimmu.2020.577823.  PMID: 33178204.  PMCID: PMC7596181.
  16. Landers VD, Wilkey DW, Merchant ML, Mitchell TC, Sokoloski KJ.  The alphaviral capsid protein inhibits IRAK1-dependent TLR signaling.  Viruses 2021 Feb 27;13(3):377.  doi: 10.3390/v13030377.  PMID: 33673546.  PMCID: PMC7997285.