TERRAINCOGNITA

T cell receptor αβ : in control of signal initiation and T cell fate

Coordinatore	UNIVERSITAETSSPITAL BASEL    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Switzerland [CH]
Totale costo	1˙930˙000 €
EC contributo	1˙930˙000 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2009-AdG
Funding Scheme	ERC-AG
Anno di inizio	2010
Periodo (anno-mese-giorno)	2010-04-01   -   2015-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAETSSPITAL BASEL  Organization address address: HEBELSTRASSE 32 city: BASEL postcode: 4031 contact info Titolo: Ms. Nome: Patricia Cognome: Zeiser Email: send email Telefono: 41615565685 Fax: 41615565685	CH (BASEL)	hostInstitution	1˙930˙000.00
2	UNIVERSITAETSSPITAL BASEL  Organization address address: HEBELSTRASSE 32 city: BASEL postcode: 4031 contact info Titolo: Prof. Nome: Ed Cognome: Palmer Email: send email Telefono: +416 12653120 Fax: +41 6 12653420	CH (BASEL)	hostInstitution	1˙930˙000.00

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 Obiettivo del progetto (Objective)

'One of the central mysteries of immunology is self-tolerance. How does the human body select ~10e12 T lymphocytes, that are reactive to foreign pathogens but tolerant to normal cellular constituents of the host? Over the last few years, my laboratory identified 2 fundamental mechanisms used by thymocytes to establish T cell tolerance. We demonstrated that the affinity threshold for negative selection is a constant for all thymocytes expressing MHC I restricted TCRs. This binding affinity threshold (KD H 6 ¼M; estimated T1/2 H 2 sec) is the fundamental biophysical parameter used by TCRs to delete autoimmune T cells. We also established how the TCR generates distinct signals for positive and negative selection. At the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signaling intermediates. The ability to compartmentalize signaling molecules differentially within the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the molecular basis for central tolerance. In the present application, we plan to fully understand 1-how the biophysical events during antigen binding to the TCR initiate an intracellular signal; 2-how these signals program an unambiguous cell fate and 3-how the system fails, when an autoimmune T cell is generated and activated. We will use a combination of transgenic and knockout mice, biochemistry and molecular imaging to fully define how the TCR functions as a molecular switch.'