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Series 01: Australian booksellers' labels, ca. 1900-ca. 2015, collected by Albert Jeffrey Bidgood

T cell receptor (TCR) transgenic mice represent an invaluable tool to study antigen-specific immune responses. In the pre-existing models, a monoclonal TCR is driven by a non-physiologic promoter and randomly integrated into the genome. Here, we create a highly efficient methodology to develop T cell receptor exchange (TRex) mice, in which TCRs, specific to the self/tumor antigen mesothelin (
Msln
), are integrated into the
Trac
locus, with concomitant
Msln
disruption to circumvent T cell tolerance. We show that high affinity TRex thymocytes undergo all sequential stages of maturation, express the exogenous TCR at DN4, require MHC class I for positive selection and undergo negative selection only when both
Msln
alleles are present. By comparison of TCRs with the same specificity but varying affinity, we show that
Trac
targeting improves functional sensitivity of a lower affinity TCR and confers resistance to T cell functional loss. By generating P14 TRex mice with the same specificity as the widely used LCMV-P14 TCR transgenic mouse, we demonstrate increased avidity of
Trac
-targeted TCRs over transgenic TCRs, while preserving physiologic T cell development. Together, our results support that the TRex methodology is an advanced tool to study physiological antigen-specific T cell behavior.
The currently available transgenic T cell receptor (TCR) models represent high affinity antigen-TCR interactions. Authors here present an alternative approach to target an exogenous TCR into the physiological Trac locus in the germline of mice, which uncovers that the natural genomic context for TCRs can enhance the antigen sensitivity of lower affinity TCRs and enables the physiologic range of antigen-TCR interaction and a gene dosage dependent mechanism of central tolerance.

Nature communications, 2023-02, Vol.14 (1), p.528-19, Article 528

Germline T cell receptor exchange results in physiological T cell development and function

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Series 01: Australian booksellers' labels, ca. 1900-ca. 2015, collected by Albert Jeffrey Bidgood

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Germline T cell receptor exchange results in physiological T cell development and function

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