Projektbeschreibung
Die Rolle des CD28-Rezeptors bei der Stimulation von T-Zellen
Für die Entwicklung eines breiten Spektrums an Therapeutika ist das Verständnis der Regulation von T-Zellen entscheidend. Die Mechanismen der Aktivierung/Repression von T-Zellen hängen von Rezeptoren ab, die nach der anfänglichen Interaktion mit Antigen-präsentierenden Zellen, die durch Proteine des wichtigsten Histokompatibilitätskomplexes gebundene Antigene aufweisen, sekundäre Signale liefern. Der CD28-Rezeptor wirkt als Co-Stimulator der T-Zellen-Aktivität. Das EU-finanzierte Projekt CD28 wird die mögliche Rolle der Sialinsäure bei der Regulierung der co-stimulierenden Aktivität von CD28 über den sogenannten Neuraminidase-Effekt untersuchen. Die strukturelle Grundlage für die CD28-Regulierung wird ebenfalls erforscht, um molekulare Plattformen zu schaffen, die zur Reaktivierung erschöpfter T-Zellen in Tumormodellen dienen können.
Ziel
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
48160 DERIO VIZCAYA
Spanien