Integrative mapping of lymphocyte signaling and function
Coordinator : R. Lesourne / L.Dupré
A critical component of the immunological response to foreign protein is the activation of T lymphocytes. T-cell receptor (TCR) recognition of peptide loaded-histocompatibility molecules (MHC) provides antigen specificity and initiates the required steps for T-cell activation and differentiation into T cell subsets with specific and adapted immune function. The recognition of peptide-MHC complexes by TCRs triggers the activation of a complex network of intracellular signaling pathways. The quality, the duration and the strength of these signals determine the outcome of T cell responses and is therefore critical for 1) the discrimination between self and non self antigens, 2) the generation and expansion of the appropriate functional T cell subsets, 3) the control of pathological disorders.
The aim of our research is to identify new molecular mechanisms involved in T cell signaling and to investigate their functional consequences on T cell responses during physiological or pathophysiological processes such as immunodeficiencies and autoimmune and disorders. Our experimental strategy is on one hand to use integrative approaches such as mass spectrometry to establish a molecular mapping of signaling networks involved in T cell activation. And on the other hand, to analyze lymphocytes from patients suffering from rare immunodeficiencies and use genetically engineered mice models to elucidate the specific function of components of these networks. Our research activity is mainly focused on molecular events associated to the T cell receptor signaling and to the remolding of actin cytoskeleton during the dynamic steps of T cell biology.
Numerous primary immunodeficiencies results from mutations on genes encoding for signalling molecules that control T cell development and function. The molecular mechanism by which many of these molecules and mutations operate remains unknown. Beyond these rare pathologies, the susceptibility to many and more frequent diseases results from the combined association of genetic variants affecting the expression and function of signalling molecules involved in T cell activation.
These defects can trigger uncontrolled reactions of T lymphocytes against healthy cells (diabetes, multiple sclerosis) or against generally harmless environmental factors (allergy). On the contrary, in some pathology they can prevent efficient T cell-dependent immune reaction (cancers). Some virus (like the HIV) or pathogenic bacteria also divert T cell signaling pathways to inhibit or control immune responses in their advantages. Understanding T cell signaling is therefore a major challenge to determine the etiology of several human pathologies and to facilitate the development of specific therapy.
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