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Associate Professor of Pharmacology and Cancer Biology
Associate Professor of Immunology
Duke University School of Medicine
Durham, NC 27710
The goal of my laboratory is to determine mechanisms that regulate cell metabolism in lymphocytes and how manipulation of cell metabolism may provide novel therapeutic approaches in inflammatory disorders and leukemia. We have shown that while normal lymphocytes rely on cell extrinsic growth signals to support cell metabolism and survival, cancer cells can maintain growth factor-independent metabolism and survival. Glucose uptake and the glucose transporter Glut1 are highly regulated in activated lymphocytes and leukemic cells. Further, activated T and B lymphocytes and acute lymphoblastic leukemic cells share a common metabolic phenotype with high levels of Glut1 expression and aerobic glycolysis. Importantly, we were the first to show that immune suppressive regulatory T cells utilize an oxidative form of metabolism that is distinct from effector and inflammatory T cells. We aim to understand molecular pathways that control Glut1 and the metabolism of functionally distinct lymphocyte populations and leukemic cells. The role of metabolism in CD4 T cell populations may provide a new opportunity to modulate immunity and we are working to better understand the metabolic pathways essential for effector and regulatory T cell development and function. Our work is highly interdisciplinary and involves the fields of immunology, cancer biology, and cell metabolism. Ultimately the goals of these projects are to exploit the specific metabolic programs of each cell type or activation state to selectively impact effector lymphocytes in inflammatory diseases and leukemic cells in cancer.
Wieman, H.L., J.A. Wofford, J.C. Rathmell. 2007. Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 kinase/Akt Regulation of Glut1 Activity and Trafficking. Mol. Biol. Cell. 18:1437-46. PMCID: PMC1838986
Wofford, J.A., H.L. Wieman, S.R. Jacobs, Y. Zhao, J.C. Rathmell. 2007. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt1 to support T cell survival. Blood. 111:2101-2111. PMCID: PMC2234050
Jacobs, S.R., C.E. Herman, J. Hammen, J.C. Rathmell. 2008. Glucose Uptake is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and -Independent Pathways. J. Immunol. 180:4476-86. PMCID: PMC2638731
Jacobs, S.R., R.D. Michalek, J.C. Rathmell. 2010. Interleukin-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol. 184:3461-9. PMID: 20194717, PMCID: PMC2980949
Mason E.F., Y. Zhao, P. Goraksha-Hicks, J.L. Coloff, H. Gannon, S.N. Jones, J.C.Rathmell. 2010. Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl. Cancer Res. 70:8066-76. PMCID: PMC2955844
Altman, B.J., S.R. Jacobs , E.F. Mason , R.D. Michalek , A.N. Macintyre, J.L. Coloff, O. Ilkayeva , W. Jia , Y-W. He, J.C. Rathmell. 2011. Autophagy is Essential to Suppress Cell Stress and to Allow BCR-Abl-Mediated Leukemogenesis. Oncogene. 30:1855-67. PMCID: PMC3081401
Michalek, R.D., V.A. Gerriets, S.R. Jacobs, A.N. Macintyre, N.J. MacIver, E.F. Mason, S.A. Sullivan, A.G. Nichols, J.C. Rathmell. 2011. Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets. J. Immunol. 186:3299-303. PMCID: PMC3198034
Coloff, J.L.*, A.N. Macintyre*, A.G. Nichols, T. Liu, C.A. Gallo, D.R. Plas, J.C. Rathmell. 2011. Akt-Dependent Glucose Metabolism Promotes Mcl-1 Synthesis to Maintain Cell Survival and Resistance to Bcl-2 Inhibition. Cancer Res. 71:5204-5213. PMCID: PMC3148426. *These authors contributed equally
MacIver, N.J.*, J. Blagih*, D.C. Saucillo, L. Tonelli, J.C. Rathmell*, R.G. Jones*. 2011. The Liver Kinase B1 (LKB1) is a central regulator of T cell development, activation, and metabolism. J. Immunol. 187:4187-4198. PMCID: PMC3206094. *These authors contributed equally.
Michalek, R.D., V.A. Gerriets, A.G. Nichols, M. Inoue, D. Kazmin, C-Y Chang, M.A. Dwyer, E.R. Nelson, K.N. Pollizzi, O. Ilkayeva, V. Giguere, W.J. Zuercher, J.D. Powell, M.L. Shinohara, D.P. McDonnell, J.C. Rathmell. 2011. The Estrogen Related Receptor-α is a Metabolic Regulator of Effector T Cell Activation and Differentiation. Proc. Natl. Acad. Sci USA. 108:18348-53. PMCID: PMC3215012
MacIver, N.J., R.D. Michalek, J.C. Rathmell. 2013. Metabolic Regulation of T Lymphocytes. Annu Rev Immunol. 31:259-283. PMCID: PMC3606674
Saucillo, D.C., V.A. Gerriets, J. Sheng, J.C. Rathmell, N.J. MacIver. 2014. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol. 192:136-44. PMCID: PMC3872216
Freemerman, A.J., A.R. Johnson, G.N. Sacks, J.J. Milner, E.L. Kirk, M.A. Troester, A.N. Macintyre, P. Goraksha-Hicks, J.C. Rathmell, L. Makowski. 2014. Metabolic reprogramming of macrophages: glucose transporter (GLUT1)-mediated glucose metabolism drives a pro-inflammatory phenotype. J. Biol. Chem. 289:7884-96. PMCID: PMC3953299
Caro-Maldonado, A., R. Wang, A.G. Nichols, M. Kuraoka, S. Milasta, L.D. Sun, A.L. Gavin, E.D. Abel, G. Kelsoe, D.R. Green, J.C. Rathmell. 2014. Metabolic Reprogramming is Required for Antibody Production That is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B Cells. J. Immunol. 192:3626-36. PMCID: PMC3984038
A.N. Macintyre*, V.A. Gerriets*, A.G. Nichols, R.D. Michalek, M.C. Rudolph, D. Deoliveira, S.M. Anderson, E.D. Abel, B.J. Chen, L.P. Hale, J.C. Rathmell. 2014. The Glucose Transporter Glut1 is Selectively Essential for CD4 T Cell Activation and Effector Function. Cell Metab. 20:61-72. PMCID: PMC4079750. *These authors contributed equally. This paper was selected for the issue cover.
Gerriets, V.A., R.J. Kishton, A.G. Nichols, A.N. Macintyre, M. Inoue, O. Ilkayeva, P.S. Winter, X. Liu, B. Priyadharshini, M.E. Slawinska, L. Haeberli, C. Huck, L.A. Turka, K.C. Wood, L.P. Hale, P.A. Smith, M.A. Schneider, N.J. MacIver, J.W. Locasale, C.B. Newgard, M.L. Shinohara, J.C. Rathmell. 2014. Metabolic Programming and PDHK1 Control CD4 T-Cell Subsets and Inflammation. J. Clin. Invest. doi: 10.1172/JCI76012. [Epub ahead of print]. PMID: 25437876
Huynh, A. M. Dupage, B Priyadharshini, P.T. Sage, C.M. Borges, N. Townamchai, V.A. Gerriets, J.C. Rathmell, A.H. Sharpe, J.A. Bluestone, L.A. Turka. 2015 Control of PI(3) kinase in Treg cells maintains lineage stability. Nat Immunol. Jan 5. doi: 10.1038/ni.3077. [Epub ahead of print]