Department Affiliation: Primary: Oncology; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Ph.D., Emory University School of Medicine
Rank: Associate Professor
Telephone Number: 410-502-7887
Fax Number: 410-614-9705
E-mail address: poweljo@jhmi.edu
School of Medicine Address: Room 443, Cancer Research Bldg., 1650 Orleans Street, Baltimore, MD 21231
Mechanisms of T cell activation and tolerance
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. Using this technique we 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 induce a negative genetic program which inhibits T cell function and promotes tolerance. 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. This receptor is upregulated by TCR engagement and plays a role in inhibiting T cell function. Furthermore, we have been able to demonstrate that A2aR activation can lead to T cell tolerance in the form of anergy and the upregulation of regulatory T cells. Activating the receptor with A2aR agonists can promote tolerance and inhibit autoimmune disease. Interestingly, there is a relatively high concentration of adenosine in the tumor micro-environment which serves to inhibit T cell function and promote anti-tumor specific tolerance. In this regard, 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.
A third gene that emerged from our screen is the DNA methyl transferase DNMT3a. DNMT3a is selectively upregulated in T cells upon antigen recognition and our data suggest it plays an important role in regulating T cell differentiation. For example, T cells from DNMT3a null mice fail to methylate IFN-g and IL-4 genes during Th2 and Th1 skewing and thus simultaneously produce both cytokines. Currently, we are exploring the role of DNMT3a in the regulation of Th17 and regulatory T cells as well as determining how manipulating DNMT3a function might affect auto and tumor immunity.
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.
Representative Publications:
- Safford, M., Collins, S., Lutz, M., Allen, A., Huang, C.T., Kowalski, J., Blackford, A., Horton, M., Drake, C.G., Schwartz, R.H., Powell, J.D. Egr-2 and Egr-3 are negative regulators of T cell activation. Nature Immunology, 6(5):472-80, 2005. Pub Med Reference.
- Powell, J.D., Fitzhugh, C., Kang, E.M., Hsieh, M., Schwartz, R.H., Tisdale, J.F. Low-Dose Radiation Plus Rapamycin Promotes Long-Term Bone Marrow Chimerism. Transplantation 80(11):1541-1545, 2005. Pub Med Reference.
- Collins, S., Wolfraim, L.A., Drake, C.G., Horton, M.R., Powell, J.D. Cutting Edge: TCR-induced NAB2 enhances T cell function by coactivating IL-2 transcription. J Immunol. 177(12):8301-8305, 2006. Pub Med Reference.
- Zheng, Y., Collins, S., Lutz, M.A., Allen, A.N., Kole, T.P., Zarek, P.E., Powell, J.D. A role for the mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol. 178(4):2163-2170, 2007. Pub Med Reference.
- 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. 111(1):251-259, 2007. Pub Med Reference.
- 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. 319(5862):476-481, 2008. Pub Med Reference.
- Delgoffe, G.M., Kole, T.P., Zheng, Y., Zarek, P.E., Matthews, K.L., Xiao, B., Worley, P.F., Kozma, S.C., Powell, J. D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 30(6):832-844, 2009. Pub Med Reference
- Delgoffe, G.M., Kole. T.P., Cotter, R.J., and Powell, J.D. Enhanced interaction between Hsp90 and raptor regulates mTOR signaling upon T cell activation. Molecular Immunology 46(13):2694-2698, 2009. Pub Med Reference
- Gamper, C.J., Agoston, A.T., Nelson, W.G., and Powell, J.D. Identification of DNA Methyltransferase 3a as a T cell Receptor-induced regulator of Th1 and Th2 differentiation. Journal of Immunology 183(4):2267-2276, 2009. Pub Med Reference
- Zheng, Y., Delgoffe, G.M., Meyer, C.F., Chan, W., Powell, J.D. Anergic T cells are metabolically anergic. Journal of Immunology (Accepted for publication).
Other graduate programs in which Dr. Powell participates:
Immunology Graduate Program
Anti-Cancer Drug Development Program
