Description du projet
Le rôle du récepteur CD28 dans la stimulation des lymphocytes T
Il est essentiel de comprendre la régulation des lymphocytes T en vue de développer un vaste éventail de thérapies. Les mécanismes d’activation/répression des lymphocytes T dépendent des récepteurs qui fournissent des signaux secondaires, après l’interaction initiale avec les cellules présentant des antigènes liés à des protéines du complexe majeur d’histocompatibilité. Le récepteur CD28 agit comme un co-stimulateur de l’activité des lymphocytes T. Le projet CD28, financé par l’UE, explorera le rôle possible de l’acide sialique dans la régulation de l’activité costimulatrice du CD28 via l’effet dit de neuraminidase. La base structurelle de la régulation induite par le CD28 sera également étudiée, ce qui permettra de créer des plateformes moléculaires qui pourraient servir à réactiver les lymphocytes T épuisés dans les modèles tumoraux.
Objectif
Regulation of T cells has been a cornerstone in the development of therapeutics for fighting a wide plethora of pathologies, including cancer, chronic infections and disease. The mechanisms governing activation or repression of T cells depend on several receptors which provide “second signals” following the initial interaction with APCs presenting MHC complexes. Among these receptors, CD28 constitutes the main interest for this project. Its role as co-stimulator of T cell activity is known for so long. However, the particular mechanisms underlying its effective interaction with its cognate ligands (CD80/CD86) remain unclear yet. In particular, the present project is aimed at exploring the possible role of sialic acid in regulation of CD28 co-stimulatory activity (via inhibition), which could provide a novel explanation for the so-called “neuraminidase effect” described for decades. This effect leads to enhanced antigen-mediated T cell activation when sialic acids are enzymatically removed, but its origin is uncertain. Additionally, the structural basis for CD28 regulation will be explored, putting an special emphasis on its exploitation for the design of molecular platforms which may serve for reactivation of exhausted T cells in tumor models. The proposed project will be jointly undertaken by two renowned groups with large and solid experience in the field of glycomics, at CIC bioGUNE (J. Jiménez-Barbero) and Scripps (J.C. Paulson). The applicant, under their guidance, will develop the project from a very wide and cross-disciplinar perspective, covering all unknown aspects related to CD28 so far as well as proposing a novel methodology to translate this knowledge into valuable goods for society. The success of the project will likewise have a remarkable impact in the field of immunotherapy-based treatments for patients with cancer or chronic infections.
Champ scientifique
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Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
48160 DERIO VIZCAYA
Espagne