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 utilization in hematopoietic stem cell differentiation, 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:
1.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; Pouzolles et al., Curr Opin Hem, 2016; Figure 1).
2.T cell reactivity and 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. Under lymphopenic conditions, antigen-specific CD4 cells are necessary to promote the differentiation of memory-like CD8 T cells into effectors with responsiveness to self antigen (Le Saout et al., PNAS, 2008; PLoS One, 2010) and more recently, we have 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 are being exploited for the utilization of CAR/TCR-engineered T cells in anti-tumor immunotherapy strategies (Figure 2). Moreover, in collaboration with Philippe Jay and colleagues, we found that Th2 differentiation in the small intestine is dependent on IL25 secretion by epithelial Tuft cells (Gerbe et al., Nature 2016).
3.Metabolic regulation of T cell activation, differentiation and retroviral infection.
The discovery by Marc Sitbon and colleagues 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 their group in the IGMM, 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 (Figure 3; Loisel-Meyer et al., PNAS 2012) and our recent studies show that the differential use of glutamine and glucose conditions T cell differentiation and function. Furthermore, high Glut1 promotes effector cytokine secretion (Cretenet et al., Scientific Reports 2016) while glutamine deprivation promotes the conversion of naïve T cells to a suppressor fate (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). The importance of metabolism in T cell activation is also highlighted by our recent studies showing that the resveratrol polyphenol alters the effector function of human T cells via changes in their bioenergetic homeostasis (Craveiro/Cretenet et al. Science Signaling, in press).
4.Regulation of hematopoietic stem cell differentiation by nutrient transporter expression and function.
Hematopoietic stem cell (HSC) renewal and lineage differentiation are finely tuned processes, regulated by cytokines, transcription factors and cell-cell contacts. However, recent studies have shown that fuel utilization also conditions HSC fate. Intriguingly, 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). Indeed, Glut1 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 (Figure 4; Oburoglu et al., Cell Stem Cell, 2014; Oburoglu et al, Curr Opin Hem, 2016). These results support ongoing work on nutrient transport/ utilization as regulators of HSC development and suggest that aberrant metabolic reprogramming contributes to pathological lineage differentiation.