- Associate Director, Bloomberg~Kimmel Institute for Cancer Immunotherapy
- Professor of Oncology
- Professor of Pharmacology and Molecular Sciences
Bone Marrow Transplant, Medical Oncology
Cancer Immunotherapy; Mechanisms of T cell activation and tolerance; Bone Marrow Transplantation
Our laboratory is interested in understanding the biochemical and molecular pathways that govern T cell activation versus tolerance.
The 2 signal model provides the framework for our understanding of T cell responses. Signal 1 refers to T Cell Receptor (TCR) recognition while Signal 2 refers to engagement of costimulatory receptors by ligands present on activated antigen presenting cells. Using high throughput microarray analysis we have uncovered several novel TCR-induced genes and pathways that play critical roles in dictating the outcome of antigen recognition. We identified the Early Growth Response (EGR) family of transcription factors as playing an important role in determining the fate of TCR recognition. Indeed, Egr-2 and Egr-3 null T cells induce more aggressive autoimmune disease but also are more effective in mounting anti-tumor responses. A second pathway that was revealed by our screen involves activation of the adenosine A2aR. Activating the receptor with A2aR agonists can promote tolerance and inhibit autoimmune disease. Alternatively, by employing A2aR null mice and specific antagonists, the lab is interested in blocking the ability to tumor-derived adenosine to inhibit T cell function and thus enhance the efficacy to tumor vaccines. In this regard the lab is involved in the preclinical development of A2aR antagonists as a means of enhancing tumor vaccines.
In addition to Signal 1, we are also interested in understanding how accessory signals derived from the environment (Signal 2) regulate T cell activation and function. Along these lines we have identified the evolutionarily conserved Serine/Threonine kinase the mammalian Target of Rapamycin (mTOR) as playing a central role in dictating the outcome of antigen recognition. By engineering mice to delete mTOR in T cells we have determined that mTOR activation is critical for Th1, Th2 and Th17 differentiation. Furthermore, in the absence of mTOR T cells differentiate down a Foxp3+ regulatory T cell pathway. Currently, we are engineering T cell specific Rheb, Rictor and TSC2 null mice in order to dissect the upstream and downstream signaling pathways responsible for regulating T cells. In addition, by taking a proteomic approach we are seeking to identify novel substrates specifically involved in dictating mTOR-induced T cell differentiation. Clinically, we have been able to exploit our findings to develop novel regimens to promote graft acceptance and inhibit Graft Versus Host Disease. Indeed, in collaboration with investigators at the NIH we have devised a novel treatment protocol to employ non-myeloablative stem cell transplantation for the treatment of sickle cell disease.
Lab Website: Jonathan D. Powell Lab
Pollizzi KN, Sun IH, Patel CH, Lo YC, Oh MH, Waickman AT, Tam AJ, Blosser RL, Wen J, Delgoffe GM, Powell JD. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol. 2016 Jun;17(6):704-11. doi: 10.1038/ni.3438. Epub 2016 Apr 11. PubMed PMID: 27064374; PubMed Central PMCID: PMC4873361.
Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, Delgoffe GM, Powell JD. mTORC1 and mTORC2 selectively regulate CD8? T cell differentiation. J Clin Invest. 2015 May;125(5):2090-108. doi: 10.1172/JCI77746. Epub 2015 Apr 20. PubMed PMID: 25893604; PubMed Central PMCID: PMC4463194.
Heikamp EB, Patel CH, Collins S, Waickman A, Oh MH, Sun IH, Illei P, Sharma A, Naray-Fejes-Toth A, Fejes-Toth G, Misra-Sen J, Horton MR, Powell JD. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol. 2014 May;15(5):457-64. doi: 10.1038/ni.2867. Epub 2014 Apr 6. PubMed PMID: 24705297; PubMed Central PMCID: PMC4267697.
Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011 Apr;12(4):295-303. doi: 10.1038/ni.2005. Epub 2011 Feb 27. PubMed PMID: 21358638; PubMed Central PMCID: PMC3077821.
Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009 Jun 19;30(6):832-44. doi: 10.1016/j.immuni.2009.04.014. PubMed PMID: 19538929; PubMed Central PMCID: PMC2768135.
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The Bloomberg~Kimmel Institute: Dr. Jonathan Powell