Coreceptor control of T cell cross-reactivity. (360G-Wellcome-079848_Z_06_Z)

£633,868

T cells recognise foreign' peptide fragments, in the context of self' major histocompatibility complex (MHC) molecules on the surface of host cells. Recognition orchestrates the immune response to protect against pathogen attack. The detection of T-cell antigens is unique inreceptor recognition because it involves the binding of both receptor (T-cell receptor; TCR) and coreceptor (CD8 or CD4). The TCR is also unique in that it must cross-react with > 106 different peptide antigens to ensure complete coverage of the array of possible permutations generated from 20 amino acid residues. This inherent cross-reactivity requires precise developmental regulation to ensure that the peripheral T-cell repertoire is optimally poised to respond in the face ofT cells recognise foreign' peptide fragments, in the context of self' major histocompatibility complex (MHC) molecules on the surface of host cells. Recognition orchestrates the immune response to protect against pathogen attack. The detection of T-cell antigens is unique inreceptor recognition because it involves the binding of both receptor (T-cell receptor; TCR) and coreceptor (CD8 or CD4). The TCR is also unique in that it must cross-react with > 106 different peptide antigens to ensure complete coverage of the array of possible permutations generated from 20 amino acid residues. This inherent cross-reactivity requires precise developmental regulation to ensure that the peripheral T-cell repertoire is optimally poised to respond in the face ofdanger while remaining continuously quiescent in the presence of self. Preliminary data indicate thatthe coreceptor controls and optimizes T-cell cross-reactivity. I will use a combinatorial peptide library approach and mutant MHC molecules that exhibit > 1000-fold range of coreceptor binding whilemaintaining faithful TCR interactions to: Assess how the coreceptors influence T-cell cross-reactivity Examine the role of CD8 sialylation in cross-reactivity Assess coreceptor-mediated T cell cross-reactivity in different species. This work has potentially important implications for our understanding of autoimmunity and could inform therapeutic interventions.

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Grant Details

Amount Awarded 633868
Applicant Surname Wooldridge
Approval Committee Clinical Interview Committee
Award Date 2006-07-12T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Intermediate Clinical Fellowship
Internal ID 079848/Z/06/Z
Lead Applicant Prof Linda Wooldridge
Partnership Value 633868
Planned Dates: End Date 2013-08-31T00:00:00+00:00
Planned Dates: Start Date 2006-11-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Wales
Sponsor(s) Prof Paul Morgan