The research of our group has focused on various aspects of human and murine T cell differentiation and responsiveness in the context of genetic and acquired immunodeficiencies as well as cancers. We have also pursued extensive studies on the role of nutrient transporters and nutrient utilisation in hematopoietic stem cell differentiaton, in general, and T cell effector function, in particular. Our strategy of combining fundamental and translational approaches has promoted our research efforts, bringing new insights in several different arenas:
Modulating T cell differentiation by thymus-targeted gene and cell therapies.
Hematopoietic stem cell transplantation (HSCT), the conventional therapy for patients with severe combined immunodeficiency, has a sub-optimal outcome in patients lacking histocompatible sibling donors. We have developed an intrathymic targeting approach to improve in vivo gene transfer and stem cell differentiation in a murine model of ZAP-70 deficiency (Adjali et al., PNAS, 2005; Adjali et al J Clin Invest, 2005) and have achieved high level intrathymic gene transfer in macaques (Moreau et al., Mol Therapy, 2009). These studies have also furthered our fundamental understanding of progenitor cell homing and lymphoid cell commitment, both in normal and SCID conditions and most notably, they have provided the first evidence that the thymus can, under certain conditions, support an autonomous differentiation (Vicente et al., Blood 2010; de Barros et al., Blood 2013; Stem Cells, 2013).
Enhancing anti-tumor T cell immunotherapy.
To improve immunotherapy strategies, the identification of factors and parameters that enhance the survival and reactivity of adoptively-transferred tumor-specific T cells is critical. Our recent studies have shown that under lymphopenic conditions, antigen-specific CD4 cells are necessary to promote the differentiation of memory-like CD8 T cells into effectors and this interaction is required for response to self antigen (Le Saout et al., PNAS, 2008; PLoS One, 2010). We have also found that the fate of adoptively-transferred T cells is conditioned by the lymphopenia-inducing regimen, due to differential effects on stromal and antigen-presenting cell subsets. These fundamental studies have resulted in the initiation of a clinical protocol using antigen receptor-redirected T cells in patients with oesophago-gastric cancer and metastatic melanoma (FP6/FP7 ATTACK projects).
Role of Glut1 and nutrient transporters in T cell activation, differentiation and retroviral infection.
The discovery that the glucose transporter Glut1 is the receptor for the human T cell leukemia virus (Manel et al., Cell, 2003) has fostered our continued collaborative studies with the group of M Sitbon, studying the role of this glucose transporter in T cell differentiation, activation and retroviral infection. We found that expression of Glut1 renders thymocytes and T cells significantly more susceptible to HIV infection (Loisel-Meyer et al., PNAS 2012) and our recent studies show that the differential use of glutamine and glucose conditions T cell differentiaton and function. Remarkably, activation of naïve CD4+ T cells under conditions of glutamine deprivation causes them to terminally differentiate into regulatory T cells (Klysz et al., Science Signaling 2015) and glutamine-derived CTP is required for efficient T cell activation, with mutations resulting in immunodeficiency (Martin et al., Nature 2014).
Regulation of hematopoietic stem cell differentiation by nutrient transporter expression and function.
We have also focused on the role of Glut1 in erythroid differentiation as the human erythrocyte is the cell type expressing the highest level of this transporter (>200,000 molecules/cell). Notably, we found that erythroid Glut1 expression is not a common trait across species but rather is restricted to those few mammals unable to synthesize ascorbic acid (AA) from glucose; comprising higher primates, guinea pigs and fruit bats. In these species, erythroid Glut1 preferentially transports an oxidized form of vitamin C, L-dehydroascorbic acid (DHA), likely providing a compensatory mechanism for those species that have lost the ability to synthesize the essential amino acid metabolite (Montel-Hagen et al., Cell, 2008; Blood, 2008). Most recently, we have identified fuel resource availability as a critical regulator of HSC commitment and differentiation to distinct lineage fates. Glutamine fuels erythroid specification via nucleotide biosynthesis and blocking glutaminolysis diverts HSCs to the myelomonocytic lineage (Oburoglu et al., Cell Stem Cell, 2014 ; Oburoglu et al, Curr Opin Hem, 2016). These results reveal nutrients as previously unsuspected regulators of HSC lineage differentiation.
Selected publications :
Gerbe, F., Sidot, E., Smyth, D. J., Ohmoto, M., Matsumoto, I., Dardalhon, V., Cesses, P., Garnier, L., Pouzolles, M., Brulin, B., Bruschi, M., Harcus, Y., Zimmermann, V. S., Taylor, N., Maizels, R. M. and Jay, P.(2016).Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites Nature . 529 : 226-30
Klysz, D., Tai, X., Robert, P. A., Craveiro, M., Cretenet, G., Oburoglu, L., Mongellaz, C., Floess, S., Fritz, V., Matias, M. I., Yong, C., Surh, N., Marie, J. C., Huehn, J., Zimmermann, V., Kinet, S., Dardalhon, V. and Taylor, N. (2015). Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation Sci Signal . 8 : ra97
Oburoglu, L., Tardito§, S., Fritz§, V., de Barros§, S. C., Merida§, P., Craveiro, M., Mamede, J., Cretenet, G., Mongellaz, C., An, X., Klysz, D., Touhami, J., Boyer-Clavel, M., Battini, J. L., Dardalhon, V., Zimmermann, V. S., Mohandas, N., Gottl (2014). Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification Cell Stem Cell . 15 : 169-84
de Barros, S. C., Vicente, R., Chebli, K., Jacquet, C., Zimmermann, V. S. and Taylor, N. (2013).Intrathymic progenitor cell transplantation across histocompatibility barriers results in the persistence of early thymic progenitors and T-cell differentiation Blood . 121 : 2144-53
Loisel-Meyer, S., Swainson, L., Craveiro, M., Oburoglu, L., Mongellaz, C., Costa, C., Martinez, M., Cosset, F. L., Battini, J. L., Herzenberg, L. A., Atkuri, K. R., Sitbon, M., Kinet, S., Verhoeyen, E. and Taylor, N.(2012).Glut1-mediated glucose transport regulates HIV infection Proc Natl Acad Sci U S A . 109 : 2549-54
Montel-Hagen, A., Kinet, S., Manel, N., Mongellaz, C., Prohaska, R., Battini, J. L., Delaunay, J., Sitbon, M. and Taylor, N. (2009).Species diversity in GLUT expression and function Cell . 137 : 201-2