Associate Professor, Faculty of Medicine, Université Libre de Bruxelles
Associate Professor, Faculty of Medicine and Pharmacy, Université de Mons
Degrees and relevant experienceBSc in Zoology, Université de Liège, Liège, Belgium
PhD in Immunology, Royal Postgraduate Medical School, University of London, London, UK
Postdoctoral training, Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland
Senior Scientist, Clinical Research Institute of Montreal, Montreal, Canada
Current research interests
- Metabolism of chronically-stimulated T cells
Proteomic analyses have shown that chronically-stimulated CD4+ T cells present a specific deficit in the expression of numerous metabolic enzymes and, consequently, exhibit a low basal glycolytic flux and a limited respiratory capacity. Interestingly, though blockade of the inhibitory receptor PD-1 restored rapid effector function in chronically-stimulated T cells, it did not shift their metabolic requirement towards aerobic glycolysis as observed in immunocompetent CD4+ T cells. Effector function was nevertheless dependent on oxidative phosphorylation, required mTORC1 activity and correlated with an apparent specific provision to spare metabolic resources of the cell. Thus, chronically-stimulated CD4+ T cells have a glycolysis-independent capacity to produce rapid effector function. As a whole, our results could have important implications in the design of immunotherapies for the prevention and treatment of chronic diseases, such as cancer and chronic infection. After PD-1-directed immunotherapy, chronically-stimulated T cells could gain indeed the potential to develop effector function in specific tissue environments where nutrient supply could limit T cell metabolism. Further work is currently undertaken to verify this hypothesis in human T cells.
- Role of lactate fluxes in T cell function
Increased glycolytic flux in cells causes lactic acid accumulation with a consequent drop in intracellular pH. This, in turn, slow down glycolysis and ATP production. Therefore, limiting excessive concentration of lactic acid in the cytoplasm is required in cell types relying on glycolysis for proliferation and function. Lactic acid efflux from cells is carried out by some members of the Slc16 gene family, the monocarboxylate transporters MCT1 and MCT4. These transporters catalyse the proton-linked transport of monocarboxylates such as L-lactate, pyruvate and ketone bodies across the plasma membrane, of which L-lactate is quantitatively by far the most important substrate. The exact role of MCT family transporters, MCT1, 2, 3 and 4, in T cell activation has not been directly established. However, pharmacological inhibition of the monocarboxylate transporter MCT1 was recently shown to inhibit T cell proliferation and allograft rejection. We take advantage of mice whose CD4+ T cells are genetically invalidated for monocarboxylate transporter expression to identify the exact role played by the these molecules in T cell development and function.
Related publicationsBettonville M, D'Aria S, Braun MY. Metabolic programming in chronically stimulated T cells: lessons from cancer and viral infections. Eur J Immunol. 2016 In press.
Weatherly K, Bettonville M, Torres D, Kohler K, Goriely S, Braun MY. Functional profile of S100A4-deficient T cells. Immun Inflamm Dis. 2015. 3 (4):431–444
Zhang J., P. Vandevenne, H. Hamdi, M. Van Puyvelde, A. Zucchi, M. Bettonville, K. Weatherly, A. Baudart, F. Gaudray, P. Lybaert, F. Libert & M.Y. Braun. MicroRNA-155-mediated Control of Heme Oxygenase 1 is Required for Restoring the Function of Exhausted CD4+ T Cells. 2015. Eur.J.Immunol. 45:829-842
Zhang J. & M.Y. Braun. PD-1 Deletion Restores Susceptibility to Experimental Autoimmune Encephalomyelitis in miR-155-deficient Mice. 2014. Int. Immunol. 26:407-415.
Noval Rivas, M., M. Hazzan, K. Weatherly, F. Gaudray, I. Salmon & M.Y. Braun. NK cells regulate graft-versus-host disease by limiting the antigen-driven expansion of CD4-positive T cells. 2010. J. Immunol. 184:6790-6798.
Noval Rivas, M., K. Weatherly, M. Hazzan, B. Vokaer, S. Dremier, F. Gaudray, M. Goldman, I. Salmon & M.Y. Braun. Reviving function in CD4 T cells adapted to persistent systemic antigen. 2009. J. Immunol. 183:4284-4291.