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Exploring new avenues to develop tomorrow’s medical knowledge through an approach that integrates basic and clinical research
Our research units are led by principal investigators who collaborate in a spirit of collegiality and with the vision of bridging the gap between research and patients. They train the next generation of scientists and are independent and creative minds who work tirelessly to improve health.
Current research
Immunobiology of T cells
Cellular differentiation is a fundamental process that occurs in vast majority of living organisms. T lymphocytes provide an outstanding paradigm for understanding novel molecular mechanisms of differentiation. In the last two decades, my research program has focused on understanding the molecular events that orchestrate T cell differentiation during the immune response. My laboratory investigates the molecular mechanisms underlying efficient CD8+ T cell response to infection, cancer and vaccination. CD8+ T cells are potent cells of the adaptive immune system able to eradicate intracellular infections, control chronic infections and eliminate tumors. A better understanding of the mechanisms regulating their response is essential to develop new strategies to fight infections and cancer. Our work focuses on the roles of: 1) the Notch signaling pathway; 2) the NR4A family members of orphan nuclear receptors; 3) circadian rhythms; and 4) the UCH family of deubiquitinases.
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Ongoing Projects
The Notch signalling pathway : a master regulator of CD8+ T cell differentiation.
Notch signaling is an evolutionarily conserved pathway controlling cell fate specification. The engagement of Notch receptors by their ligands leads to translocation of the Notch intracellular domain (NICD) to the nucleus where it associates with RBPJ to induce gene transcription. We demonstrated that Notch signaling is a key orchestrator of CD8+ T cell differentiation (Mathieu et al. 2015 JI; Chung et al. 2019 JI; De Sousa et al. 2019 Plos One; Perkey et al. 2020 JI). Following vaccination or acute infection, early Notch signals provided by stromal cells promote the generation of short-lived effector T cells (SLECs). At the molecular level, Notch controls the transcription of a T-cell specific gene set, including genes known to be modulated by cytokine signals (manuscript in preparation). Moreover, during acute infection, Notch signals restrain the differentiation of CD8+ resident memory T cells developing in non-barrier tissues. During chronic infection, continued Notch signaling is required to prevent severe CD8+ T cell exhaustion. In the absence of Notch signals in CD8+ T cells, more exhausted CD8+ T cell progenitors are generated but they fail to differentiate into effector-like exhausted T cells (manuscript in preparation). We will test the hypotheses that: i) the Notch signaling pathway controls different aspects of the CD8+ T cell fate depending on the spatiotemporal cellular context, which leads to a unique transcriptional program; and ii) manipulation of the Notch signaling pathway can be used to improve the CD8+ T cell response to infection and cancer.
Regulation of CD8+ T cell responses by the orphan nuclear receptor NR4A3 :
We have recently uncovered unique and essential roles for the orphan nuclear receptor NR4A3 in the CD8+ T cell response. NR4A3 is one of the three members of the NR4A nuclear receptor subfamily, whose expression is rapidly and transiently induced in CD8+ T cells following T cell receptor (TCR) stimulation. We have shown that NR4A3 deficiency enhances cytokine production by effector and memory CD8+ T cells while favouring the generation of central memory CD8+ T cells (Odagiu et al. 2020. PNAS). As such, adoptive immunotherapy with NR4A3 deficient CD8+ T cells more efficiently controls tumor growth than with wild-type counterparts. Our hypothesis is that NR4A3 defines CD8+ T cell fates and functions during acute and chronic responses by modulating the expression of specific sets of target genes.
The role of UCH family deubiquitinases in T cell biology
Recent scientific efforts have been largely made towards understanding T cell gene expression changes at different stages of its life. However a full picture of regulation of cell fate and function requires that we explore further the events that occur specifically at the protein level. One of the most important cellular regulatory mechanisms is mediated by a modification of proteins termed ubiquitylation, where a small ubiquitin molecule or chain of ubiquitins is added to a protein. This modification can result in the targeted protein’s destruction but also in a change in its activity or cellular localization. Specialized enzymes called deubiquitinases (DUBs) can remove ubiquitin molecules. Our research will focus on the UCH family of DUBs, which is vastly understudied in T cell biology. We have demonstrated that one member of this family, BAP1, is important in the response of CD8+ T cells as its overexpression in CD8+ T cells decreases their expansion and inhibits SLEC differentiation following Listeria infection. Furthermore, BAP1 also forms a multi-protein complex in T cells as reported in other cell types. We will test the hypothesis that UCH DUBs play critical roles in T cell differentiation and function.
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