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Title: The role of germline-encoded T cell receptor complementarity determining regions in T cell selection and function
Author: Holland, Stephen
ISNI:       0000 0004 2732 1656
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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αβ T cell Receptors (TCR) recognise peptide antigen (p) presented on Major Histocompatability Complexes (MHC) via Complementarity Determining Regions (CDRs). TCRs are required to respond to a vast plethora of differing antigens and the CDR regions are suitably diverse, encoded by an array of gene-segments, which recombine during T cell development to generate diverse repertoires of TCRs. CDR1 and 2, which predominantly interact with the MHC, are encoded within gene-segments, and are subject to evolutionary pressure. However, CDR3 loops are non-germline and created through junctional diversity. TCRs are ‘MHC restricted’ and only respond to antigen in the context of MHC. An influential theory proposes that CDR1 and 2 have co-evolved with MHC and as such are inherently predisposed towards MHC recognition. This thesis used preliminary data derived from whole genome analysis of TCR CDR1 and 2 diversity relative to those of related immunoglobulins (which are not MHC restricted) to determine if there is any relationship between germline CDR diversity and MHC restriction. Conventional mutagenesis involving substituting CDR1 and 2 with artificial peptide linkers and replacement of βCDR1 and 2 with those of the related yet MHC unrestricted γTCR chain was carried out in concert with a novel system that embedded recombination cassettes into the CDR1 or 2 allowing in vivo generation and selection of a library of non-germline CDR1 or 2 mutants. Collectively, these data strongly infer a lack of requirement of germline CDR sequences in mediating MHC recognition in both pMHC-mediated T cell development and function. However, alteration of the germline sequence did affect the efficiency of T cell development, preference of MHC class type and the diversity of the subsequent T cell repertoire. Thus, germline CDR structures may facilitate a more diverse array of MHC docking modes to maximise the resultant TCR repertoire, contributing to an increased capacity for cross-reactivity, rather than imposing MHC restriction.
Supervisor: Dyson, Julian ; George, Andrew Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral