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.
Clinical Trial Keywords:
- Powell, J.D. The induction and maintenance of T cell anergy. Clinical immunology (Orlando, Fla. 2006 Sep;120(3):239-246.
- Scheibner, K.A.; Lutz, M.A.; Boodoo, S.; Fenton, M.J.; Powell, J.D.; Horton, M.R. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006 Jul 15;177(2):1272-1281.
- Durakovic, N.; Radojcic, V.; Powell, J.; Luznik, L. Rapamycin promotes emergence of IL-10-secreting donor lymphocyte infusion-derived T cells without compromising their graft-versus-leukemia reactivity. Transplantation. 2007 Mar 15;83(5):631-640.
- Durakovic, N.; Radojcic, V.; Skarica, M.; Bezak, K.B.; Powell, J.D.; Fuchs, E.J.; Luznik, L. Factors governing the activation of adoptively transferred donor T cells infused after allogeneic bone marrow transplantation in the mouse. Blood. 2007 May 15;109(10):4564-4574.
- Zarek, P.E.; Powell, J.D. Adenosine and anergy. Autoimmunity. 2007 Sep;40(6):425-432.
- Zheng, Y.; Collins, S.L.; Lutz, M.A.; Allen, A.N.; Kole, T.P.; Zarek, P.E.; Powell, J.D. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol. 2007 Feb 15;178(4):2163-2170.
- Collins, S.; Lutz, M.A.; Zarek, P.E.; Anders, R.A.; Kersh, G.J.; Powell, J.D. Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol. 2008 Jan 17;38(2):528-536.
- Huang, G.N.; Huso, D.L.; Bouyain, S.; Tu, J.; McCorkell, K.A.; May, M.J.; Zhu, Y.; Lutz, M.; Collins, S.; Dehoff, M.; Kang, S.; Whartenby, K.; Powell, J.; Leahy, D.; Worley, P.F. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science. 2008 Jan 25;319(5862):476-481.
- Luznik, L.; O'Donnell, P.V.; Symons, H.J.; Chen, A.R.; Leffell, M.S.; Zahurak, M.; Gooley, T.A.; Piantadosi, S.; Kaup, M.; Ambinder, R.F.; Huff, C.A.; Matsui, W.; Bolanos-Meade, J.; Borrello, I.; Powell, J.D.; Harrington, E.; Warnock, S.; Flowers, M.; Brodsky, R.A.; Sandmaier, B.M.; Storb, R.F.; Jones, R.J.; Fuchs, E.J. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-650.
- Zarek, P.E.; Huang, C.T.; Lutz, E.R.; Kowalski, J.; Horton, M.R.; Linden, J.; Drake, C.G.; Powell, J.D. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood. 2008 Jan 1;111(1):251-259.
- Bolanos-Meade, J.; Luznik, L.; Muth, M.; Matsui, W.H.; Huff, C.A.; Smith, B.D.; Levy, M.Y.; Kasamon, Y.L.; Swinnen, L.J.; Powell, J.D.; Brodsky, R.A.; Ambinder, R.F.; Jones, R.J.; Fuchs, E.J. Salvage transplantation for allograft failure using fludarabine and alemtuzumab as conditioning regimen. Bone Marrow Transplant. 2009 Mar;43(6):477-480.
- Delgoffe, G.M.; Powell, J.D. mTOR: taking cues from the immune microenvironment. Immunology. 2009 Aug;127(4):459-465.
- Gamper, C.J.; Agoston, A.T.; Nelson, W.G.; Powell, J.D. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009 Aug 15;183(4):2267-2276.
- Kasamon, Y.L.; Luznik, L.; Leffell, M.S.; Kowalski, J.; Tsai, H.L.; Bolanos-Meade, J.; Morris, L.E.; Crilley, P.A.; O'Donnell, P.V.; Rossiter, N.; Huff, C.A.; Brodsky, R.A.; Matsui, W.H.; Swinnen, L.J.; Borrello, I.; Powell, J.D.; Ambinder, R.F.; Jones, R.J.; Fuchs, E.J. Nonmyeloablative HLA-Haploidentical BMT with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome. Biol Blood Marrow Transplant. 2009 Nov 16.
- Scheibner, K.A.; Boodoo, S.; Collins, S.; Black, K.E.; Chan-Li, Y.; Zarek, P.; Powell, J.D.; Horton, M.R. The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am J Respir Cell Mol Biol. 2009 Mar;40(3):251-259.
- Zheng, Y.; Delgoffe, G.M.; Meyer, C.F.; Chan, W.; Powell, J.D. Anergic T cells are metabolically anergic. J Immunol. 2009 Nov 15;183(10):6095-6101.
- Gamper, C.J.; Powell, J.D. Genetic and biochemical regulation of CD4 T cell effector differentiation: insights from examination of T cell clonal anergy. Immunol Res. 2010 Jul;47(1-3):162-171.
- Gulen, M.F.; Kang, Z.; Bulek, K.; Youzhong, W.; Kim, T.W.; Chen, Y.; Altuntas, C.Z.; Sass Bak-Jensen, K.; McGeachy, M.J.; Do, J.S.; Xiao, H.; Delgoffe, G.M.; Min, B.; Powell, J.D.; Tuohy, V.K.; Cua, D.J.; Li, X. The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity. 2010 Jan 29;32(1):54-66.
- Horton, M.R.; Powell, J.D. Quieting T cells with Slfn2. Nat Immunol. 2010 Apr;11(4):281-282.
- Kasamon, Y.L.; Jones, R.J.; Brodsky, R.A.; Fuchs, E.J.; Matsui, W.; Luznik, L.; Powell, J.D.; Blackford, A.L.; Goodrich, A.; Gocke, C.D.; Abrams, R.A.; Ambinder, R.F.; Flinn, I.W. Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol. 2010 Jun;21(6):1203-1210.
- Kasamon, Y.L.; Luznik, L.; Leffell, M.S.; Kowalski, J.; Tsai, H.L.; Bolanos-Meade, J.; Morris, L.E.; Crilley, P.A.; O'Donnell, P.V.; Rossiter, N.; Huff, C.A.; Brodsky, R.A.; Matsui, W.H.; Swinnen, L.J.; Borrello, I.; Powell, J.D.; Ambinder, R.F.; Jones, R.J.; Fuchs, E.J. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010 Apr;16(4):482-489.
- Luznik, L.; Bolanos-Meade, J.; Zahurak, M.; Chen, A.R.; Smith, B.D.; Brodsky, R.; Huff, C.A.; Borrello, I.; Matsui, W.; Powell, J.D.; Kasamon, Y.; Goodman, S.N.; Hess, A.; Levitsky, H.I.; Ambinder, R.F.; Jones, R.J.; Fuchs, E.J. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010 Apr 22;115(16):3224-3230.
- Powell, J.D.; Delgoffe, G.M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010 Sep 24;33(3):301-311.