Our group is studying T cell homeostasis in the context of patients with genetic and viral immunodeficiencies. T cell fate following retroviral-mediated gene transfer/infection as well as IL-7 and self-antigen stimulation are being explored in human as well as murine models.
Modulation of 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 are involved in preclinical gene transfer studies for patients with mutations in ZAP-70, a tyrosine kinase that plays a crucial role in the activation and development of T cells. We have recently demonstrated enhanced T cell reconstitution when vectors and stem cells were targeted to the thymus. Studies of the dynamics of this differentiation are ongoing
T cell homeostasis. IL-7 differentially affects neonatal T lymphocytes, which have only recently emigrated from the thymus, as compared to peripheral blood lymphocytes in adults, with significantly increased proliferation of the former cells. We are studying the biology of IL-7 responses and its potential clinical use in lymphopenia, such as following stem cell transplantation or symptomatic HIV infection (with Cytheris Inc).
Genetic modification of T lymphocytes. Genetically modified lymphocytes are being evaluated as therapies for multiple disorders. We are presently involved in a FP6 integrated project aimed at achieving TCR gene transfer in T cells in order to optimize anti-tumor responsiveness (ATTACK). Studies are underway to enhance gene transfer into cytokine-stimulated T cells.
HTLV, Glut-1 and cell metabolism. Together with the group of M. Sitbon, we identified GLUT-1, the ubiquitous glucose transporter, as an HTLV receptor. We recently determined that expression of GLUT-1 characterizes a specific stage of human thymocyte development and are presently studying the role of GLUT-1 in the differentiation of CD34+ stem cells. Moreover, are now focusing on how interactions between the HLTV envelope and GLUT-1 modulate the biology of various T cell subsets, mother-to-infant transmission and spreading of HTLV.
T cell activation in response to self-antigens: Tolerance and autoimmunity. The interplay among CD8 + T killer cells, CD4 + T helper cells and antigen presenting cells (APCs) plays an important role in the onset of T cell-mediated autoimmune diseases. Present experiments are aimed at deciphering the cellular and molecular interactions responsible for the establishment of T cell tolerance to self-antigens vs. the activation of auto-reactive T cells leading to autoimmune diabetes.