Research Summary
The Jonathan D. Powell 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 the 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 the lab has uncovered several novel TCR-induced genes and pathways that play critical roles in dictating the outcome of antigen recognition. They identified the Early Growth Response (EGR) family of transcription factors as playing an important role in determining the fate of TCR recognition. 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 their 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, the lab is also interested in understanding how accessory signals derived from the environment (Signal 2) regulate T cell activation and function. Along these lines they 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, they 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, they 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 the lab is seeking to identify novel substrates specifically involved in dictating mTOR-induced T cell differentiation. Clinically, the lab has been able to exploit their findings to develop novel regimens to promote graft acceptance and inhibit Graft Versus Host Disease. In collaboration with investigators at the NIH, they have devised a novel treatment protocol to employ non-myeloablative stem cell transplantation for the treatment of sickle cell disease.
Lab
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
Clinical Trial Keywords
immunotherapy
Selected Publications
View all on Pubmed
Leone, RD; Zhao, L; Englert, JM; Sun, IM; Oh, MH; Sun, IH; Arwood, ML; Bettencourt, IA; Patel, CH; Wen, J; Tam, A; Blosser, RL; Prchalova, E; Alt, J; Rais, R; Slusher, BS; Powell, JD. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019 Nov;366(6468):1013-1021
Patel, CH; Leone, RD; Horton, MR; Powell, JD. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat Rev Drug Discov. 2019 Sep;18(9):669-688
Hess, BM; Thomas, DG; Weber, TJ; Hutchison, JR; Straub, TM; Bruckner-Lea, CJ; Powell, JD; Kabilan, S; Corley, RA. An integrated experimental-computational approach for predicting virulence in New Zealand white rabbits and humans following inhalation exposure to Bacillus anthracis spores. PLoS One. 2019 Jul;14(7):e0219160
Larimer, C; Brann, MR; Powell, JD; Marshall, MJ; Suter, JD; Addleman, RS. Rapid nondestructive measurement of bacterial cultures with 3D interferometric imaging. Sci Rep. 2019 May;9(1):8055
Vigeland, CL; Beggs, HS; Collins, SL; Chan-Li, Y; Powell, JD; Doerschuk, CM; Horton, MR. Inhibition of glutamine metabolism accelerates resolution of acute lung injury. Physiol Rep. 2019 Mar;7(5):e14019
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