Perreault, Claude, M.D.

Research axis

• Immunology and Haematopoiesis
• Stem cells
• Cancer
• Systems biology

Research description

Claude Perreault and his team at IRIC focus their research initiatives on three questions:

1. What is the molecular definition of the immune self? Self/non-self discrimination is a fundamental requirement of life. While unicellular eukaryotes primarily employ self/nonself discrimination to avoid self-mating and germline parasitism, multicellular organisms use self/nonself discrimination primarily in immune defence. In a remarkable example of convergent evolution, agnathans and jawed vertebrates have evolved adaptive immune systems based on somatically diversified and clonally expressed Ag receptors. Somatic diversification conveys a decisive advantage in recognition of nonself but comes at a price: some Ag receptors on adaptive lymphocytes happen to be self-reactive. Furthermore, recognition of self has a pervasive influence on the development and function of the immune system because the adaptive lymphocytes of jawed vertebrates are eminently self-referential: they are selected on self-molecules, sustained by self-molecules, and activated in the presence of self-molecules. This raises the fundamental question: what is the molecular definition of self for the adaptive immune system? In our effort to understand the genesis of the immune self, we focus mainly on the self recognized by CD8 T cells, that is, peptides presented by MHC I molecules (the immunopeptidome). We have recently discovered that the immunopeptidome is extremely plastic and that it projects at the cell surface a representation of biochemical networks and metabolic events regulated at multiple levels inside the cell. Since perturbation of a single signaling pathway can lead to significant changes in the composition of the immunopeptidome, cells can communicate their metabolic status to the adaptive immune system. The plasticity of the immunopeptidome has important implications in immunobiology. Depending on the context, inclusion of new peptides in the immunopeptidome can initiate tumor rejection or autoimmunity. Ongoing projects seek to understand how different types of proteasomes and genomic polymorphisms (the genomic self) impact the immunopeptidome (the immune self)This multidisciplinary research program is performed in collaboration with the teams of Pierre Thibault and Sébastien Lemieux.
2. Adoptive T-cell immunotherapy (ATCI) of cancer. Allogeneic hematopoietic cell transplantation (AHCT) led to the discovery of the allogeneic graft-versus-leukemia (GVL) effect, which remains the most convincing evidence that immune cells can cure cancer in humans. However, despite its great paradigmatic and clinical relevance, induction of GVL by conventional AHCT remains a quite rudimentary form of leukemia immunotherapy. It is toxic and its efficacy is far from optimal. It is therefore sobering that since the discovery of the GVL effect three decades ago, the way GVL is induced and manipulated has practically not changed. Pre-clinical and clinical studies suggest that injection of T cells primed against a single antigen (Ag) present on neoplastic cells could enhance the GVL effect without causing any toxicity to the host. We therefore contend that Ag-targeted ATCI represents the future of cancer immunotherapy and we are evaluating different strategies to reach this goal. Differences between these strategies hinge on two key elements: the nature of the target Ag and the type of Ag receptor expressed on T cells.
3. Homeostasis of thymic epithelial cell progenitors. The thymus, the primary T lymphoid organ in all animals with an adaptive immune system, has both its structure and function remarkably conserved. The conservation of the thymus over 450 million years of evolution and the lack of any thymus equivalent or substitute in the animal kingdom is remarkable when one considers, for instance, that about ten different organs have been used as primary sites of hematopoiesis in gnathostomes. No other organ can compensate for defective thymic function. This is problematic since progressive thymus atrophy ultimately affects all ageing subjects and can even impinge on younger subjects affected by several serious illnesses. Thymus senescence is the most common immunopathology in humans. The rapid and irreversible attrition of thymic epithelial cells is very intriguing considering that other epithelia (skin, GI tract) display an enormous self-renewal potential. We therefore seek to understand the biology of thymic epithelial cell progenitor/stem cells and to elaborate strategies to rejuvenate the thymus.