Our central hypothesis is that Foxp3 deficiency destabilizes Foxp3-deficient Treg cells (ΔTreg) towards an effector T (Teff) cell-like program in a stepwise process that can be reversed to re-establish their regulatory functions. Specifically, the degeneration from ΔTreg cells to Teff-like cells involves the transition from a CD25+Foxp1high cell population into the CD25–Foxp1low activated Teff-like cells, both epigenetically related to Treg cells, and ultimately emerge as ex-Treg cells losing the Treg cell epigenetic imprint. Our aim is to understand the molecular mechanisms underlying the different steps of ∆Treg degeneration.
About Louis-Marie’s Charbonnier’s lab
Louis-Marie's Charbonnier's lab is focused on regulatory T (Treg) cell destabilization and reprogramming in the context of autoimmunity and primary immunodeficiencies. Of particular interest is the role of Foxp3 and among other factors that contribute to regulatory T cell fitness and homeostasis. The research program is oriented in cellular and molecular immunology to elucidate mechanisms of human immune dysregulatory diseases and develop curative therapies.
1. Stepwise degeneration of Foxp3-deficient Regulatory T cells:
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2. Metabolic reprogramming of regulatory T cells
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We have previously shown that Foxp3 deficiency leads to increased glycolysis and oxidative phosphorylation of ΔTreg cells through a mTORC2-dependent mechanism (Charbonnier et al. 2019). Based on these observations, we hypothesize that Treg drastic metabolic changes underlie the destabilization and degeneration. In this regard, our group is investigating the relevance of different metabolic pathways by using both pharmacologic and ΔTreg-specific target gene deletion to restore immune tolerance and prevent autoimmunity.
3. Perturbations of hematopoiesis in the context of Treg cell dysfunction
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Hematopoiesis exclusively occurs in the bone marrow at steady state; however, Foxp3 deficiency leads to the presence of myeloid and lymphoid progenitors in peripheral secondary lymphoid organs and highly vascularized tissues such as liver and lungs. Our lab is interested in investigating the role of inflammation and production of GM-CSF by Teff and ∆Treg cells in Foxp3-deficient mice as well as the contribution of the extramedullary hematopoiesis in the pathogenesis of autoimmunity.
4. Immune dysregulation in the pathogenesis of the hyper IgE (HIES) syndrome
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Our central hypothesis is that the causative mutations of HIES, including STAT3, DOCK8, PGM3, ZNF341 and IL6R/IL6ST, all act to compromise RORgt+ Treg cell differentiation, leading to gut dysbiosis and weakened protection against infections normally imparted by the commensal bacteria. Accordingly, augmenting RORgt+ Treg cell differentiation by means of commensal bacterial signals or metabolite therapy is predicted to suppress the hyper IgE response, correct the dysbiosis and ameliorate the severity of the disease. To test our hypothesis is currently being tested using mouse models of HIES as well as patient samples.