Professor David Price
The diversity of T cell antigen receptors is generated by recombination of germline V(D)J gene segments, CDR3 nucleotide additions and deletions, and TCR chain association to yield a functional heterodimeric receptor. After thymic editing, the diversity of the naïve T cell receptor repertoire in humans approximates to 2.5 x 107. From this available pool, adaptive immune responses must be mounted rapidly to all relevant threats without significant reactivity against self. The potential number of antigen complexes that could theoretically be encountered within the context of a given MHC genotype vastly exceeds the available T cell repertoire in the periphery. However, this discrepancy does not compromise the host due to an inherent degree of cross-reactivity in the process of T cell recognition, such that a given TCR can productively engage with multiple different pMHC complexes. The corollary of this cross-reactivity is that any single pMHC complex can potentially be recognized by multiple different TCRs; thus, a given antigen-specific T cell response can comprise multiple different clonotypes. The clonotypic composition of an individual antigen-specific T cell response is likely to depend on the nature of the antigen and the conditions under which it is encountered. However, the rules that govern clonal selection in the periphery remain poorly defined.
Aims:
1. To characterize the clonal architecture of T cell responses specific for defined antigens from distinct sources under a spectrum of conditions directly ex vivo;
2. To characterize the properties of individual constituent clonotypes within these antigen-specific T cell responses directly ex vivo;
3. To investigate the biological relevance of antigen-specific T cell repertoire composition in the pathogenesis of disease; and,
4. To investigate new approaches to antigen delivery that might enable the manipulation of clonotype usage in response to given antigens with beneficial effect.