How to find a therapeutic TCR
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D'Ippolito, E. et al. Needle in a Haystack: The Naive Repertoire as a Source of T Cell Receptors for AdoptiveTherapy with Engineered T Cells.
Sublethal infection of mice with the Gram-positive bacterium Listeria monocytogenes results in the development of very effective and long-lasting protective immunity, mediated primarily by CD8+ and CD4+ Listeria-specific T cells. Using MHC multimer reagents, we want to characterize the determinants of effective protective immunity in this experimental model: how, when and where are Listeria-specific memory T cell populations generated in vivo? What is the contribution of different Listeria-specific subpopulations (defined by their lineage, epitope-specificity, phenotype, functional status) to protective immunity? Is there functional interaction/synergism between different Listeria-specific T cell subpopulations which is important for the quality of protective immunity? Different experimental strategies are used to address these questions (e.g. gene knockout mice, transgenic mice, ENU mutagenesis). These studies are designed to shed light on the basic requirements for effective protective immunity; a better understanding of immunological memory will facilitate the development of new, more effective vaccine strategies. An additional clinical application of MHC tetramers is the diagnostic monitoring of antigen-specific T cell immunity.
MHC multimer technology allows both identification and isolation of epitope-specific T cells. Especially with the help of the recently developed reversible MHC-multimer staining (Streptamers) it may be possible to purify and adoptively transfer epitope-specific T cell populations into recipients, a technique that would have broad clinical applications. We are pursuing the development of methods to efficiently purify tetramer-positive T cells and prepare them for adoptive transfer. Adoptive transfer of epitope-specific T cells will initially be tested in the murine Listeriosis model in order to address some basic experimental questions: Is it possible to transfer pathogen-specific protective immunity into naïve individuals by adoptive transfer of purified tetramer-positive, epitope-specific T cells? What are the minimal requirements (absolute number, epitope specificity, lineage, functional status) for effective adoptive transfer of protective immunity? Similar studies will be performed in other experimental models (e.g. chronic infections).